SMJ

E-ISSN 2228-8082

Volume 75, Number 5, May 2023

Siriraj Medical Journal

The world-leading biomedical science of Thailand

MONTHLY ORIGINAL ARTICLE

Indexed by

THAILAND SECTION 1954

https://he02.tci-thaijo.org/index.php/sirirajmedj/index

E-mail: sijournal92@gmail.com

By Suveerawan Limsuvan, et al.

Siriraj Medical Journal SMJ‌

Volume 75, Number 5, May 2023

ORIGINAL ARTICLE

321 The Effect of the Thai Herbal Wattana Formula on Platelet Aggregation and the Relationship with Innate Dhatu Chao Ruean

Pravit Akarasereenont, et al.

330 Outcomes Comparison of Early versus Late Surfactant Replacement Therapy in Neonates with Respiratory Distress Syndrome

Chutinun Wongkhonkaen, et al.

343 Transvaginal Urethrolysis as a Treatment Option for Women with Recurrent Cystitis

Sunporn Boonwong, et al.

350 The Relationship between Kolb Learning Style and Academic Performances in Orthopedic Residents

Cherdsak Iramaneerat, et al.

356 Routine Fogarty Catheter Occlusion of Fistula in Esophageal Atresia with Tracheoesophageal Fistula Surgery: A Retrospective Study

Darunee Sripadungkul, et al.

362 The Feasibility and Outcomes of Retrograde Intrarenal Surgery to Treat Staghorn Renal Calculi

Sunai Leewansangtong, et al.

369 Validity and Reliability of the Thai version of the Family Dermatology Life Quality Index

Kanokvalai Kulthanan, et al.

377 Adverse Events of Traditional Medicines and Herbal Products in the Thai Health Product Vigilance

Center Database and the Ayurved Clinic of Applied Thai Traditional Medicine, Siriraj Hospital

Suvimol Niyomnaitham, et al.

392 Sleep Quality and Associated Factors in Elderly Patients with Type-2 Diabetes Mellitus

Sitthichai Khamchet, et al.

REVIEW ARTICLE

399 Current Physical Therapy Management and Clinical Evaluation for Achilles Tendinopathy

Sangarun Dungkong

SMJ

SIRIRAJ MEDICAL JOURNAL

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Executive Editor: Apichat Asavamongkolkul Editorial Director: Aasis Unnanuntana

Editor-in-Chief: Thawatchai Akaraviputh, Mahidol University, Thailand

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Varut Lohsiriwat, Mahidol University, Thailand

Andrew S.C. Rice, Imperial College London, UK

International Editorial Board

Morris Solomon Odell, Monash University, Australia

Anusak Yiengpruksawan, The Valley Robotic Institute, USA Barbara Knowles, The Jackson Laboratory, USA Christopher Khor, Singapore General Hospital, Singapore Ciro Isidoro, University of Novara, Italy

David S. Sheps, University of Florida, USA

David Wayne Ussery, University of Arkansas for Medical Sciences, USA Davor Solter, The Jackson Laboratory, USA

Dennis J. Janisse, Medical College of Wisconsin, USA

Dong-Wan Seo, University of Ulsan College of Medicine, Republic of Korea Folker Meyer, Argonne National Laboratory, USA

Frans Laurens Moll, University Medical Center Ultrecht, Netherlands

G. Allen Finley, Delhousie University, Canada

George S. Baillie, University of Glasgow, United Kingdom

Gregory Bancroft, London School of Hygiene of Tropical Medicine, United Kingdom Gustavo Saposnik, St. Michael’s Hospital, Canada

Harland Winter, Harvard Medical School, USA

Hidemi Goto, Nagoya University Graduate School of Medicine, Japan Ichizo Nishino, National Institute of Neuroscience NCNP, Japan Intawat Nookaew, University of Arkansas for Medical Sciences, USA James P. Doland, Oregon Health & Science University, USA

John Damian Smith, Texas A&M University-San Antonio, USA John Hunter, Oregon Health & Science University, USA

Juri Gelovani, Wayne State University, USA

Karl Thomas Moritz, Swedish University of Agricultural Sciences, Sweden Kazuo Hara, Aichi Cancer Center Hospital, Japan

Keiichi Akita, Tokyo Medical and Dental University Hospital, Japan Kym Francis Faull, David Geffen School of Medicine, USA

Kyoichi Takaori, Kyoto University Hospital, Japan Marcela Hermoso Ramello, University of Chile, Chile Marianne Hokland, University of Aarhus, Denmark

Matthew S. Dunne, Institute of Food, Nutrition, and Health, Switzerland Mitsuhiro Kida, Kitasato University & Hospital, Japan

Moses Rodriguez, Mayo Clinic, USA

Nam H. CHO, Ajou University School of Medicine and Hospital, Republic of Korea Nima Rezaei, Tehran University of Medical Sciences, Iran

Noritaka Isogai, Kinki University, Japan

Paul James Brindley, George Washington University, USA

Pauline Mary Rudd, National Institute for Bioprocessing Research and Training Fosters Avenue Mount Merrion Blackrock Co., Dublin, Ireland

Peter Hokland, Aarhus University Hospital, Denmark

Philip A. Brunell, State University of New York At Buffalo, USA Philip Board, Australian National University, Australia

Richard J. Deckelbaum, Columbia University, USA Richard W. Titball, University of Exeter, USA Robert W. Mann, University of Hawaii, USA

Robin CN Williamson, Royal Postgraduate Medical School, United Kingdom Sara Schwanke Khilji, Oregon Health & Science University, USA

Seigo Kitano, Oita University, Japan

Shomei Ryozawa, Saitama Medical University, Japan Shuji Shimizu, Kyushu University Hospital, Japan

Stanlay James Rogers, University of California, San Francisco, USA Stephen Dalton, University of Georgia, USA

Sue Fletcher, Murdoch University, Australia

Tai-Soon Yong, Yonsei University, Republic of Korea Tomohisa Uchida, Oita University, Japan

Victor Manuel Charoenrook de la Fuente, Centro de Oftalmologia Barraquer, Spain Vincent W.S. Chan, University of Toronto, Canada

Wen-Shiang Chen, National Taiwan University College of Medicine, Taiwan Wikrom Karnsakul, Johns Hopkins Children’s Center, USA

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Yozo Miyake, Aichi Medical University, Japan Yuji Murata, Aizenbashi Hospital, Japan

Ampaiwan Chuansumrit, Mahidol University, Thailand Anuwat Pongkunakorn, Lampang Hospital, Thailand Jarupim Soongswang, Mahidol University, Thailand Nopphol Pausawasdi, Mahidol University, Thailand Nopporn Sittisombut, Chiang Mai University, Thailand Pa-thai Yenchitsomanus, Mahidol University, Thailand Pornchai O-Charoenrat, Mahidol University, Thailand Prapon Wilairat, Mahidol University, Thailand Puttinun Patpituck, Mahidol University, Thailand Rungroj Krittayaphong, Mahidol University, Thailand Saranatra Waikakul, Mahidol University, Thailand

Editorial Board

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Vitoon Chinswangwatanakul, Mahidol University, Thailand Watchara Kasinrerk, Chiang Mai University, Thailand Wiroon Laupattrakasem, Khon Kaen University, Thailand Yuen Tanniradorn, Chulalongkorn University, Thailand

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The Effect of the Thai Herbal Wattana Formula on Platelet Aggregation and the Relationship with Innate Dhatu Chao Ruean

Suveerawan Limsuvan, M.Sc.*, Titchaphorn Palo, M.Sc.**, Dollaporn Mamaethong, B.ATM. *, Nut Yuthanarat, B.ATM. *, Suksalin Booranasubkajorn, Ph.D.*, Natchagorn Lumlerdkij, Ph.D.*, Kamonchanok Maneechai, B.ATM *, Pravit Akarasereenont, M.D., Ph.D.*,**

*Center of Applied Thai Traditional medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, **Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

ABSTRACT

Objective: To investigate the effects of the Thai Herbal Wattana formula (WNF) on platelet aggregation and find a link between Innate Dhatu Chao Ruean (iDCR) factors and platelet aggregation.

Materials and Methods: Forty healthy volunteers with different iDCRs (Earth, Water, Wind, and Fire) received a single dose of 1,000 mg WNF. A blood sample was taken before and after the WNF administration at 3, 6, and 24 hours for analysis of platelet aggregation by aggregometry. Epinephrine, adenosine diphosphate (ADP) and collagen were used as platelet agonists.

Results: The WNF affects platelet aggregation in some subjects, especially females with an Earth iDCR or Wind iDCR with hyperaggregation patterns at baseline. The result after WNF treatment revealed that the percentage of platelet aggregation significantly changed downward at 3 hours and then recovered to pre-dosing levels after 24 hours. Additionally, it also did not have any relationship to iDCR. There were no reported adverse drug events. Conclusion: WNF should be used with caution in patients with blood diseases and a close eye should be kept on herb-drug interactions such as with aspirin or other NSAIDs.

Keywords: Thai Herbal Wattana formula; WNF; Herbal medicine; Platelet aggregation; innate Dhatu Chao Ruean

(Siriraj Med J 2023; 75: 321-329)

INTRODUCTION

New trends regarding good health have generated interest in young people in society. Recently, the use of herbal medicine as an alternative or complementary therapy has increased dramatically in many parts of the world. Thai Traditional medicine refers to the knowledge, skills, and practices passed down from generations of folk healers from many cultures and is used to help maintain health against age-related deterioration, as well as prevent and treat various diseases. As a basic theory,

Thai traditional medicine considers the imbalance of four elements (Earth, Water, Wind, and Fire) as an illness. In each person, there will be one element that is more dominant. Innate Dhatu Chao Ruean (iDCR) is the dominant body element at birth. It is analyzed by the month of birth and is divided as follows: Earth, from September to November, Water, from June to August, Wind, from March to May, and Fire, from December to February.1

Corresponding authors: Pravit Akarasereenont E-mail: pravit.auk@mahidol.edu

Received 25 February 2023 Revised 20 March 2023 Accepted 21 March 2023 ORCID ID:http://orcid.org/0000-0001-9768-8347 https://doi.org/10.33192/smj.v75i5.261536

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

The Thai Herbal Wattana formula (WNF) has been used for over 40 years. It is used to help maintain health, and prevent age-related problems, such as muscle pains, loss of appetite, weaknesses, digestion, and gastrointestinal problems. The 18 medicinal plant components in the formula are Boesenbergia rotunda (L.) Mansf, Saussurea lappa C.B. Clarke., Ligusticum sinense Oliv. cv. Chuanxiong, Cinnamomum illicioides A. Chev., Carthamus tinctorius L., Mallotus repandus (Willd.) Muell. Arg., Cladogynos orientalis Zipp. ex Span., Derris scandens (Roxb.) Benth., Cryptolepis buchanani Roem. & Schult., Tinospora crispa (L.) Hook.f. & Thomson, Caesalpinia sappan L., Piper nigrum L., Ferula assa- foetida Regel, Drypetes roxburghii (Wall.) Hurusawa, Aegle marmelos (L.) Corrêa, Citrus sinensis (L.) Osbeck, Terminalia chebula Retz. and, Cyperus rotundus L. The recommended dose is 3-5 pills (200 mg/pill), 3 times per day before meals. The indication of this drug is older people (aging in Thai traditional medicine is defined as aged 32 and over). Moreover, the WNF has been investigated by many scientific studies to explain its pharmacological activities relating to age degeneration, including anti- oxidation2, immunomodulatory3,4 anti-neurodegenerative,5 and anti-inflammatory properties.6 Anti-inflammation is one effect linked to WNF’s ability to ease muscle pain compared to diclofenac in OA knee patients.7 The WNF may work similarly to NSAID inhibition. NSAIDs provide a COX inhibition that prevents synthesis of thromboxane A2. It is also effective at inhibiting platelet aggregation.8 Understanding antiplatelet medications that balance anti-thrombotic potential with the danger of bleeding is still a concern. Therefore, this study aimed to investigate the impact of the Thai Herbal Wattana formula on platelet aggregation in healthy volunteers. This will help understand the safety of the WNF and any potential unwanted side effects. Moreover, it will be interesting to investigate the relationship between factors of innate Dhatu Chao Ruean and the impact of platelet aggregation on herbal drugs to better understand specific responses to provide personalized health care.

MATERIALS AND METHODS

Study drugs

WNF pills (200 mg) and powder were manufactured under GMP PIC/S (Good Manufacturing Practices) by the Manufacturing Unit of Herbal Medicines and Products, Center of Applied Thai Traditional Medicine (CATTM), Faculty of Medicine Siriraj Hospital, Mahidol University. The experiments used the same batch of WNF pills in the study. All WNF pills were authenticated and qualified by quality control, including the FTIR method, UPLC

method, physical properties, and microbial contamination. WNF pills and powder were stored and preserved at room temperature in dry conditions.

Subject design

This controlled pre-post intervention study was conducted at the Faculty of Medicine Siriraj Hospital, Bangkok, Thailand. The protocol was approved by the Siriraj Institutional Review Board (COA no. Si 756/2019) and registered in the Thai Clinical Trials Registry (TCTR20221213002). Before enrolling in the study, participants were provided necessary information, including the risks and benefits and signed an informed consent form. For the pilot study, 40 healthy volunteers with four different innate Dhatu Chao Ruean (Earth, Water, Wind and Fire) were recruited. The following criteria was used for inclusion: 1) Thai male or female

≥ 32 years old at time of enrollment; 2) body mass index (BMI) between 18-24 kg/m2 ; 3) in good health as confirmed by blood chemistry, or an AST ≤ 40 U/L (male), ≤ 32 U/L (female); ALT ≤ 41 U/L (male), ≤ 33 U/L (female); ALP ≤ 141 U/L (male), ≤ 105 U/L (female) and GFR ≥ 60 ml/min/1.73m2. The exclusion criteria were:

1. evidence of allergic reactions from herbal medicine;

2. habitual smoking with no ability to abstain from cigarettes during the study; 3) history of excess alcohol ingestion without ability to abstain from alcohol during the study or drug abuse; 4) pregnant or breastfeeding;

5) history of blood donation or transfusion within 3 months of the study. The volunteers who had an adverse event caused by WNF or believed to have had an event as were withdrawn as per physician agreement. All participants received advice to prepare themselves prior to the study and were informed to abstain from caffeine, alcohol and intake of vitamins, dietary supplements, and foods containing any of the 18 components of the WNF for at least two weeks. Moreover, other information or concerns from volunteers was followed up on and proper advice provided. On experiment day, blood samples were drawn and kept in sodium citrate vacutainer (Greiner Bio-one GmbH, Austria) at pre-dose for baseline, 3, 6, and 24 hours after administration of 1,000 mg WNF. Moreover, vital signs and all reported adverse events were evaluated and recorded by study physicians.

Platelet aggregation assay

Platelet aggregation was determined using light transmission (LTA) and Born’s technique in an aggregometer (AggRAM, Helena, USA). LTA is the gold standard for determination of platelet aggregation by measuring the change in absorbance as platelet-rich plasma (PRP) is

agitated with reagents. Epinephrine (Epi), adenosine diphosphate (ADP), and collagen (Col) were used as a panel of platelet agonists.9 All platelet aggregation assays were run within 3 hours of blood collection. Citrated whole blood was centrifuged at 250g for 10 minutes at 25°C to prepare PRP. Some PRP was centrifuged at 4500g for two minutes at 25°C to prepare platelet-free plasma (PFP) to set as a blank. PRP was incubated at 37°C for 3 minutes before being induced with 1µM Epi, 25 µM Epi, 5 µM ADP and 1 µg/ml Col while stirring at 600 rpm. The reaction was allowed to proceed for 5 minutes. The difference between light transmissions of aggregated PRP and PFP was used to calculate the maximal amplitude of platelet aggregation as a percentage. Moreover, the platelets count was measured by using a non-metalized haemocytometer (Helena, USA).

Platelet status classification

There is still a need for a formally accepted standard for measuring platelet function. The previous method classified the function into 3 categories of aggregation based on how platelets responded to various epinephrine concentrations.10,11 The primary phase of platelet aggregation, caused by 25 µM epinephrine, is defined by the “disaggregation pattern”. In contrast, platelet aggregation caused by 1 µM epinephrine and expressed as the secondary phase of aggregation is known as the “hyperaggregation pattern”. Therefore, the concentration-dependent response of platelets to 1 µM and 25 µM epinephrine was labeled as the “normal aggregation pattern”.10,11

Statistical analysis

All data was presented as mean ± standard deviation (SD). Statistical analyses were performed with SPSS, version 18 (SPSS Inc., Chicago, IL, USA). Platelet aggregation data was evaluated for normality using the Kolmogorov– Smirnov and Shapiro-Wilk tests. Group comparisons were performed by a nonparametric Mann-Whitney U test (between gender) and the Kruskal-Wallis test (between iDCR). Time-dependent changes (before and after WNF administration) in groups were assessed by the nonparametric Friedman test; pairwise post hoc comparisons. Moreover, the chi-square statistic was used for categorical variables. Analyses were declared significant for a P-value <0.05.

RESULTS

Demographic characteristics

Forty healthy volunteers were enrolled in this study from March 2020 to August 2020. All subjects

completed the study. The average age of the male group and female group was 36.3±3.9 and 39.1±5.9, respectively. The baseline characteristics, clinical chemistry, and hematologic screening of all subjects were normal. All data was homogeneous at the baseline. There was no difference between the sex groups (Table 1).

Platelet status pattern before dosing

Before WNF treatment, 47% of the total 40 subjects exhibited the hyperaggregation pattern while 40% and 13% exhibited the normal and disaggregation pattern (Fig 1a). A comparison of, male and female platelet aggregation status before dosing did not significantly differ between the two groups (Figs. 1b1-1b2). Among the iDCR group, more than half of the subjects in the Wind group (70%) exhibited the hyperaggregation pattern (Fig 1c3). However, platelet status patterns of subjects in the Wind, Earth, Water and Fire group were not significantly different (Figs 1c1-c4).

Effect of WNF on platelet aggregation

To assess the impact of the WNF on each subject, each individual subject’s pattern of platelet aggregation stratified to sex, and iDCR is shown in Fig 2. The total result after WNF treatment revealed that the pattern of platelet aggregation status changed at 3 and 6 hours, and then recovered to pre-dosing levels after 24 hours. In the female group, especially those in the Earth or Wind iDCR, the hyperaggregation pattern was almost downward (Fig 2). The percentage of platelet aggregation for each agonist is shown as a heat map in Fig 3. The average of the percentages of aggregation decreased at 3 and 6 hours and then reverted to pre-dosing levels after 24 hours (Fig 4). However, the WNF also revealed an interesting trend of increased platelet aggregation classified as disaggregation status (Figs 4c1-3). In this study, platelet aggregation did not have any link to gender (Figs 4b1-4b2). Additionally, it also did not have any relationship to iDCR even if platelet aggregation in the Earth and Fire group significantly decreased after WNF treatment (Figs 4d1-4).

At each investigation time point, the average platelet counts were within an acceptable range (150-750 x 109 cells/L) and did not impair LTA experiments.12 The average platelet count of 40 PRP subjects at pre-dose, 3, 6, and 24 hours after WNF administration were 366 x

109 cells/L, 298 x 109 cells/L, 307 x 109 cells/L, and 369 x 109 cells/L, respectively. The results showed a decreasing trend at 3 and 6 hours of dosing before reverting to pre- dosing levels after 24 hours.

TABLE 1. Demographic data and baseline laboratory values with reference range criteria.

Data were determined by Mean±SD

Fig 1. Platelet aggregation pattern before and after 3, 6 and 24 hours of WNF dosing in

40 healthy volunteers (a), grouping with sex (Male: b1, Female: b2) and iDCR

(Earth: c1, Water: c2, Wind: c3 and Fire: c4)

Fig 2. The effect of WNF on platelet aggregation revealed individual patterns after 3, 6 and 24 hours.

Fig 3. Heatmap of percent platelet aggregation in each subject for each agonist after WNF administration

DISCUSSION

The Thai Herbal Wattana Formula is indicated for pain relief and anti-inflammation like NSAIDs in OA knee patients.7 A study on the WNF also revealed an anti-inflammatory impact that may be attributed to an enzyme’s COX-specific inhibitory activity.6 It is well- known that reducing thromboxane A2 production by suppressing COX enzymes affects platelet aggregation and raises the risk of bleeding.8 However, the lack of an anti-platelet aggregation study is a cause of concern about the safety of older people or blood disorders using WNF.

The aggregation pattern observed in the 40 participants of this study before treatment is similar to one observed previously in healthy subjects and is known as hyperaggregation.13,14 According to Thai

traditional medicine theory, which supports these findings, the participants’ Earth iCDR is the heaviest, slowest- changing element. Due to these reasons, no disaggregation pattern was observed. Additionally, the subjects’ Wind iCDR, which is stimulated more quickly than other iCDR components is intrinsically reflective of motion movements. Hyperaggregation may be present in the Wind element more than others.1 In our study, the WNF siginifcantly inhibited aggregatation by Epi, ADP and collagen. According to previous studies, many receptors and signaling pathways are involved in the anti-platelet aggregation impact of WNF components. PAF-induced platelet aggregation, 5-HT release by platelets, and an increase in free calcium in platelets can all be inhibited by safflower aqueous extract.15 Additionally, hydroxysafflor yellow A, safflower yellow A, luteolin and carthamin, the

Fig 4. The average of platelet aggregation of 40 subjects after WNF administration (a) sub analysis with sex (b1-2), pattern (c1-3) and iDCR (d1-4). Aggregation of platelet was induced by 1 µM Epi, 25 µM Epi, 5 µM ADP and 1 µg/ml Col. Percent aggregation of platelet after 3, 6 and 24 hours of WNF administration were compare to predose and interpreted as percent of control. Data was shown as mean ± SD. *Post- hoc Wilcoxon test by Friedman test, Significance level was set at P-value < 0.05

safflower’s active marker, can prevent ADP-controlled aggregation of human platelets.16,17 (Brazilin, isolated from heartwood of Caesalpinia sappan acts as a collagen receptor agonist.18 An extract of Cyperus rotundus in ethanol demonstrated effective inhibition of thrombin, collagen, or AA-induced platelet aggregation.19 The major active component of piper nigrum, piperine, significantly reduced AA liberation by attenuating cPLA2 activity in collagen-stimulated platelets.20 A dose-dependent reduction of AA-induced human platelet aggregation was shown with T. chebula fruit extract.21 Interpreting the effects of the WNF on platelets has been a challenge due to significant inter-individual variability in aggregation between various agonists. This could be the result of multiple pathways that lead to platelet aggregation and the involvement of numerous platelet receptors in each pathway. Additionally, each subject’s specific genetic diversity significantly impacts changing platelet responsiveness and function. In any case, additional research is still required to comprehend the mechanism.

We must be aware of platelet aggregation’s effects on the WNF in individual patients.

CONCLUSION

This study is the first to examine how the WNF affects platelet aggregation in healthy volunteers with various innate Dhatu Chao Ruean (iDCR) groups. In this investigation, there were no drug-related adverse events related to the WNF. The results suggest that 1,000 mg of WNF could impact platelet aggregation (Fig 5). Out of 40 subjects, 60% displayed a downward trend of platelet aggregation patterns (Fig 5a). Similar results were revealed by an analysis based on gender, but the female group had a trend to greater downward platelet pattern than the male group (Fig 5b). Earth, Wind, and Fire iCDR groups under investigation also showed a downward trend, while the Water iCDR group showed no change (Fig 5c). Within 24 hours, the patterns of platelet status and percent platelet aggregation changed. After being stimulated with 1 µM Epi, 25 µM Epi, 5 µM ADP and

Fig 5. The effect of the WNF on platelet aggregation is defined as the percentage of platelet aggregation pattern changing (a: 40 subjects, b: different sex, c: different iCDR) and the effect of WNF on platelet aggregation agonists of 40 subjects (d), Data is shown as mean ± SD.

*Post-hoc Wilcoxon test by Friedman test, Significance level was set at P-value < 0.05

1 µg/ml Col at 3 hours, the WNF significantly reduced the percentage of platelet aggregation (Fig 5d). Females with Earth iDCR or Wind iDCR with hyperaggregation patterns should use the WNF with caution. The effect of the WNF on platelet aggregation in an individual may be due to intrinsic influences, including iDCR and genetic variations in drug metabolizing enzymes of each volunteer. This supports calls for the concept of personalized medicine based on platelet reactivity. It should be used with caution in older adults and patients with a history of blood disorders, with special attention on herb-drug interactions, such as aspirin or other NSAIDs.

ACKNOWLEDGEMENTS

The study was financially supported by the Agricultural Research and Development Agency (Public Organization) (ARDA). The authors would like to thank the Manufacturing Unit of Herbal Medicines and Products, the Center of Applied Thai Traditional Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University for authenticated plant material and the facilities provided for the study.

REFERENCES

1. Laohapand T and Jaturatamrong U, Thai Traditional Medicine in the Faculty of Medicine Siriraj Hospital, Ayurved Thamrong School, Center of Applied Thai Traditional Medicine, Faculty of

   
   

   Medicine Siriraj Hospital, Mahidol University. Bangkok: Supavanich Press; 2009.

2. Panich U, Pluemsamran T, Tangsupa-a-nan V, Wattanarangsan J, Phadungrakwittaya R, Akarasereenont P, et al. Protective effect of AVS073, a polyherbal formula, against UVA-induced melanogenesis through a redox mechanism involving glutathione-related antioxidant defense. BMC Complement Altern Med. 2013;13:159.10 page.

3. Duangsa-ard S, Wongkajornsilp A, Akarasereenont P, Huabprasert S, Chongputtharaksa T, Laohapand T. The effects of Ayurved Siriraj Wattana recipe on splenocytes in Wistar rat. Siriraj Med J. 2013;65(3):73-6.

4. Wongkajornsilp A, Numchaisermsuk N, Sa-ngiamsuntorn K, Akarasereenont P, Wamanuttajinda V, Kasetsinsombat K, et al. Effects of the Ayurved Siriraj Wattana recipe on functional and phenotypic characterization of cytokine-induced killer cells and dendritic cells in vitro. BMC Complement Altern Med. 2016;16(489):11 page.

5. Htoo HH, Limsuvan S, Thamsermsang O, Hernandez JF, Checler F, Govitrapong P, et al. The Polyherbal Wattana Formula Displays Anti-Amyloidogenic Properties by Increasing α-Secretase Activities. PLos One. 2017;1-17.

6. Charoenkij P, Palo T, Chotewuttakorn S, Limsuvan S, Laohapand T, Akarasereenont P. The effect of Ayurved Siriraj Wattana Recipe (AVS073) on LPS induced COX-2 expression in human PBMC. Siriraj Med J. 2016;68(2):90-6.

7. Pengkhum T, Chatsiricharoenkul S, Akarasereenont P, Charoencholvanich K. Phase II clinical trial of Ayurved Siriraj Wattana recipe for symptomatic relief in patients with osteoarthritis of the knee. J Med Assoc Thai. 2012;95(3):452-60.

8. Schafer AI. Effects of nonsteroidal antiinflammatory drugs on platelet function and systemic hemostasis. J Clin Pharmacol. 1995 Mar;35(3):209-19.

9. Cattaneo M. Light Transmission Aggregometry and ATP Release for the Diagnostic Assessment of Platelet Function. Semin Thromb Hemost. 2009;35:158–67.

10. Ketsa-Ard K, Poungvarin N, Juengchareon M, Jarerat S, Kittigul

    L. Clinical study on antithrombotic effects of ticlopidine in ischemic stroke. J Med Assoc Thai. 1991;74(6):331-9.

11. Akarasereenont P, Tripatara P, Chotewuttakorn S, Palo T, Thaworn A. The effects of estrone, estradiol and estriol on

    platelet aggregation induced by adrenaline and adenosine diphosphate. Platelets. 2006;17(7):441-7.

12. Femia EA, Scavone M, Lecchi A, Cattaneo M. Effect of platelet count on platelet aggregation measured with impedance aggregometry (multiplate analyzer) and with light transmission aggregometry. J Thromb Haemost. 2013;11:2193–6.

13. Yee DL, Bergeron AL, Sun CW, Dong JF, Bray PF. Platelet hyperreactivity generalizes to multiple forms of stimulation. J Thromb Haemost. 2006;4(9):2043-50.

14. Sirikarin T, Palo T, Chotewuttakorn S, Chandranipapongse W, Limsuvan S, Akarasereenont P. The Effects of Andrographis paniculata on Platelet Activity in Healthy Thai Volunteers. Evid Based Complement Alternat Med. 2018;2018:2458281.

15. Huang D, Lu Y, Shi L, Zhang J, Shen J, Bao M, et al. Effect of safflower yellow on platelet activating factor mediated platelet activation in patients with coronary heart disease. Bangladesh J Pharmacol. 2012;7:140-4.

16. Lu PH, Kuo CY, Chan CC, Wang LK, Chen ML, Tzeng IS, et al. Safflower Extract Inhibits ADP-Induced Human Platelet Aggregation. Plants (Basel). 2021;10(6):1192.

17. Li HX, Han SY, Wang XW, Ma X, Zhang K, Wang L, et al. Effect of the carthamins yellow from Carthamus tinctorius L. on hemorheological disorders of blood stasis in rats. Food Chem Toxicol. 2009;47(8):1797-802.

18. Chang Y, Huang SKH, Lu WJ, Chung CL, Chen WL, Lu SH, et al. Brazilin isolated from Caesalpinia sappan L. acts as a novel collagen receptor agonist in human platelets. J Biomed Sci. 2013;20(4):11 page.

19. Seo EJ, Lee DU, Kwakf JH, Lee SM, Kimg YS, Jung YS. Antiplatelet effects of Cyperus rotundus and its component (+)-nootkatone. J Ethnopharmacol. 2011;135(1):48-54.

20. Son DJ, Akiba S, Hong JT, Yun YP, Hwang SY, Park YH, et al. Piperine Inhibits the Activities of Platelet Cytosolic Phospholipase A2 and Thromboxane A2 Synthase without Affecting Cyclooxygenase-1 Activity: Different Mechanisms of Action Are Involved in the Inhibition of Platelet Aggregation and Macrophage Inflammatory Response. Nutrients. 2014;6:3336-52.

21. Haq MZU, Shahid SA, Ahmed S, Ahmad S, Qayum M, Khan I. Anti-platelet activity of methanolic extract of Grewia asiatica

L. leaves and Terminalla chebula Retz. fruits. J Med Plants Res. 2012;6(10):2029-32.

Outcomes Comparison of Early versus Late Surfactant Replacement Therapy in Neonates with Respiratory Distress Syndrome

Chutinun Wongkhonkaen, M.D., Pongsatorn Paopongsawan, M.D., Junya Jirapradittha, M.D., Pakaphan Kiatchoosakun, M.D.

Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Thailand.

ABSTRACT

Objective: To compare durations of invasive mechanical ventilator (IMV), other types of ventilator support and neonatal outcomes between neonates who received early versus late surfactant replacement therapy (E-SRT vs. L-SRT). Materials and Methods: This retrospective study included neonates with gestational age (GA) less than 35 weeks or birth weight (BW) less than 2,000 grams, born between January 1, 2017 to December 31, 2021. Neonates who received SRT before 2 hours of life were defined as E-SRT and neonates who received SRT later were defined as L-SRT. Durations of IMV, other types of ventilator support, neonatal outcomes and length of stays were documented. Results: Eighty-three neonates had received SRT with 52 (62.7%) had E-SRT and 31 (37.3%) had L-SRT. Neonates in E-SRT group had significantly lower GA and BW than neonates in L-SRT group (median GA 27 vs. 30 weeks; p = 0.002 and median BW 885 vs. 1330 grams; p = 0.003) and had longer duration of IMV but not significant (median 19.0 vs. 10.5 days; p = 0.219). There were no significant differences in durations of other types of ventilator support. After adjusted for sex, GA and BW, there were no significant differences in neonatal outcomes between neonates in each group. Ventilator-associated pneumonia (VAP) and septicemia were independent factors associated with prolonged IMV, ventilator supports and length of stays.

Conclusion: Timing of SRT was not associated with duration of IMV. VAP and septicemia were important factors prolonging ventilator durations and length of stays and should be prevented.

Keywords: surfactant replacement therapy, respiratory distress syndrome, timing of surfactant, neonatal outcomes (Siriraj Med J 2023; 75: 330-342)

INTRODUCTION

Respiratory distress syndrome (RDS) is an important disease affecting preterm neonates worldwide leading to acute neonatal respiratory failure and deaths.1 Since the introduction of maternal antenatal corticosteroid injection and surfactant replacement therapy (SRT) for neonates, the mortality and morbidity rates of neonates with RDS have decreased dramatically with 30-40% reduction in neonatal mortality and 35-60% reduction

in pneumothorax and air leak syndrome.2 Improvements in non-invasive ventilation (NIV) support for neonates, for example nasal continuous positive airway pressure (NCPAP) or heated humidified high-flow nasal cannula (HHHFNC), has further decreased the need for intubation, invasive mechanical ventilation (IMV) support and SRT among neonates with mild to moderate RDS.3

However, NIV support may have been failed in some neonates with severe RDS and SRT is still necessary. For

Corresponding author: Pongsatorn Paopongsawan E-mail: pongsatorn@kku.ac.th

Received 3 February 2023 Revised 17 March 2023 Accepted 27 March 2023 ORCID ID:http://orcid.org/0000-0002-9503-4312 https://doi.org/10.33192/smj.v75i5.261175

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

these neonates, studies showed that early SRT (E-SRT) given within 2 hours of life could reduce the duration of IMV and NIV4,5 but with increased risks of air leak syndrome.6 SRT could be given by several techniques such as endotracheal tube with continuous IMV technique (ETT-IMV), intubation-surfactant-extubation technique (INSURE)7, or less-invasive surfactant administration technique (LISA).8 However, due to the high cost of surfactant, E-SRT was not given to every neonate and neonates with moderate RDS could deteriorate and eventually needed SRT later beyond 2 hours of life. Late SRT (L-SRT) may lead to prolonged IMV and respiratory complications such as bronchopulmonary dysplasia (BPD) and ventilator-associated pneumonia (VAP).9

The primary objective of the study was to compare duration of IMV between neonates with RDS receiving E-SRT and L-SRT. Other objectives included duration of NIV and oxygen therapy, treatment complications, morbidities and mortality among neonates.

MATERIALS AND METHODS

In this retrospective study, we reviewed medical documents of neonates with gestational age (GA) less than 35 weeks or birth weight (BW) less than 2,000 grams, born between January 1, 2017 and December 31, 2021, at Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Thailand, who were diagnosed with RDS and had received at least one dose of SRT. Neonates with missing or incomplete medical record would be excluded from the study.

Neonates were grouped into E-SRT group, defined as receiving SRT before 2 hours of life, and L-SRT group, defined as receiving SRT after 2 hours of life. Types of surfactants that neonates received were poractant alfa (Curosurf®, Chiesi Farmaceutici, Italy) or beractant (Survanta®, AbbVie, USA). Criteria for SRT included 1) neonates who were at risk for developing RDS (GA less than 35 weeks), 2) neonates with clinical and radiographic evidences of RDS, and 3) neonates who required FiO2 more than 40% regardless of types of ventilator support.10,11 Dosage of SRT ranged from 100-200 mg/kg of phospholipid depended on surfactant products with recommended doses were 200 mg/kg for poractant alfa and 100 mg/ kg for beractant. After first dose of SRT, if the neonates clinically deteriorated with FiO2 requirement reached 40% then additional doses of SRT could be given with time interval no less than 12 hours from each dose and no more than 3 doses in total. Dosage of subsequent SRT were 100 mg/kg of phospholipid for both poractant alfa and beractant.

SRT could be given alone or mixed with budesonide

with the aim to prevent BPD. Currently, there is no standard guideline recommending the usage of budesonide, therefore, the decision to administered budesonide was at neonatologists’ discretion based on risk for developing BPD such as neonates with GA less than 28 weeks and did not receive a completed course of antenatal corticosteroid. Neonates with risk for infection such as neonates with history of maternal chorioamnionitis or sepsis would not be given budesonide.12,13

Collected data included demographic data, maternal characteristics, types, doses and numbers of surfactants used for SRT, methods of SRT, duration of IMV and NIV, duration of oxygen therapy, complications during hospitalization such as air leak syndrome, BPD defined as neonates that needed oxygen supplement at 36 weeks postmenstrual age (PMA) according to National Institute of Child Health and Human Development (NICHD) 2018 criteria14, VAP, retinopathy of prematurity (ROP), septicemia, necrotizing enterocolitis (NEC), hemodynamically significant patent ductus arteriosus (hsPDA), mortality rate and length of hospital stays.

Statistical analyses were performed using IBM SPSS Statistics, version 26.0 (IBM Corp., Armonk, NY, USA). Percent, ratio, mean ± standard deviation (SD), mean difference, median with interquartile range (IQR) and difference of medians were used to present descriptive data. Correlation analyses were performed by using chi-square test, Fisher’s exact test, Student t-test, or Mann-Whitney U-test and presented in odd ratios. A p-value of less than 0.05 was considered to be statistically significant. Multivariate regression analysis was done to minimize confounding factors and identify possible risks associated with outcomes. This study was approved by the Ethics Committee for Human Research at Khon Kaen University (HE651192).

RESULTS

There were 434 neonates with GA less than 35 weeks or BW less than 2,000 grams born during the study period, of which 83 (19.1%) had received SRT. Among neonates that received SRT, 52 (62.7%) had E-SRT and 31 (37.3%) had L-SRT. Neonates who received E-SRT had significantly lower BW [median 885 (IQR 795,1195) vs. 1330 (IQR 895,1580) grams, difference of medians 280 (95%CI 80-485) grams; p = 0.003] and GA [median 27 (IQR 25,29) vs. 30 (IQR 27,31) weeks, difference of medians 2 (95%CI 1-3) weeks; p = 0.002] than neonates who received L-SRT. More mothers in E-SRT group had multiple medical conditions than mothers in L-SRT group though not statistically significant (30.8% vs. 22.6%; p = 0.116). Multiple gestation was the

most common medical condition among mothers in E-SRT group while hypertension was the most common condition among mothers in L-SRT group. Also, twin- twin transfusion syndrome and acardiac twins were found only among mothers in E-SRT group. Mothers in both groups similarly received antenatal corticosteroid

and medications. Mothers in E-SRT group tended to have more complications of pregnancy than mothers in L-SRT group but not statistically significant (90.4% vs. 74.2%; p = 0.093). Neonatal and maternal characteristics were shown in Table 1.

TABLE 1. Neonatal and maternal characteristics.

TABLE 1. Neonatal and maternal characteristics. (Continued)

Abbreviations: SRT = surfactant replacement therapy, SGA = small for gestational age, AGA = appropriate for gestational age, LGA = large for gestational age, † = median and interquartile range, * = statistically significant, HBsAg = hepatitis B surface antigen, VDRL = venereal disease research laboratory, § = could have more than one conditions, PROM = premature rupture of membrane

Surfactant and respiratory support characteristics

Neonates in E-SRT group were intubated more than neonates in L-SRT group (92.3% vs. 70.9%; p = 0.010), and were mostly intubated immediately at labor room while neonates in L-SRT group were mostly intubated later at neonatal intensive care unit (NICU). Neonates in E-SRT group were supported by IMV more than L-SRT group (86.5% vs. 29.0%; p < 0.001) and the most frequently used ventilator mode was conventional mode.

The most common surfactant used in each group was poractant alfa followed by poractant alfa mixed with budesonide. Neonates in E-SRT group received more of poractant alfa mixed with budesonide than neonates in L-SRT group although not significant (25.0% vs. 6.4%; p = 0.099). Dosage of surfactant used for SRT was similar between each group (158 ± 31 vs. 152 ± 24 mg/kg; p = 0.976). The median of timing of SRT in E-SRT and L-SRT group were 1.4 and 5.0 hours, respectively (p < 0.001).

The most common technique for SRT was ETT- IMV technique in both groups but neonates in E-SRT group received more SRT via ETT-IMV technique than neonates in L-SRT group (90.4% vs. 51.6%; p < 0.001). Also, more neonates in E-SRT group required multiple doses of SRT than L-SRT group (23.1% vs. 6.5%; p = 0.044). Surfactant types, SRT techniques and ventilator characteristics were shown in Table 2.

Duration of ventilator supports

Among 83 neonates, 70 neonates were intubated using IMV support with 48 in E-SRT group and 22 in L-SRT group. Overall median of IMV duration was

14.5 (IQR 3.0,32.0) days. Duration of IMV in E-SRT group was longer than L-SRT group but not statistically significant [median 19.0 (IQR 3.0,35.0) days vs. 10.5 (IQR 2.0,28.0) days; difference of medians 3.0 days (95%CI

-1.0 to 14.0); p = 0.219]. At the age of 60 days, neonates in L-SRT group had significantly higher IMV-free days [median 49.5 (IQR 32.0-58.0) days] than neonates in E-SRT group [median 25.0 (IQR 0.0-42.5) days; p < 0.001].

There were 72 neonates receiving NIV support with 41 in E-SRT group and 31 in L-SRT group. Eleven neonates died during IMV and had never received NIV support. Among neonates who received NIV, duration of NIV support was longer in E-SRT group than L-SRT group though not statistically significant [median 42.5 (IQR 26.5,54.0) days vs. 31.0 (IQR 13.0,51.0) days; p = 0.239].

However, neonates in L-SRT group had significantly higher NIV-free days at the age of 60 days than neonates

in E-SRT group [median 20.0 (IQR 0.0,41.0) days vs. 0.0 (IQR 0.0,22.0) days; p = 0.034].

Duration of oxygen usage had a similar trend with IMV and NIV duration, with neonates in L-SRT had higher oxygen free days at the age of 60 days than E-SRT group [median 16.0 (IQR 0.0,36.0) days vs. 0.0 (IQR

0.0,23.0) days; p = 0.041].

There were no significant differences in oxygen usage at 28 days, oxygen usage at 36 weeks PMA and home oxygen usage between neonates of each group. Durations of ventilator supports and oxygen supplements were shown in Table 3.

Other outcomes

There were 13 neonates who died before discharge, all of which were in E-SRT group. Neonates in E-SRT group tended to have higher rates of IVH, air leak syndrome, hsPDA, septicemia, VAP, and NEC than neonates in L-SRT group. However, after adjusted for sex, GA and BW, none of the aforementioned outcomes was significantly different.

Among 70 neonates who survived until the timing of diagnosis, ROP and BPD were higher among neonates in E-SRT group than L-SRT group but after adjustment for sex, GA and BW, the difference became insignificant. BPD severity did not differ significantly among neonates in each group, however, rate of stage 3 ROP was higher among neonates in E-SRT group (p = 0.015). Also, 10 neonates (25.6%) in E-SRT group required treatment for ROP while none of neonates in L-SRT group needed treatment (p = 0.004).

Length of hospital stays between neonates in E-SRT group (mean 70 ± 44 days) and L-SRT group (mean 72 ± 35 days) was similar between both groups (mean difference 1.7 days, 95%CI (-16.8) to 20.3 days; p = 0.853). Other outcomes of neonates were shown in Table 4.

Characteristics of non-surviving neonates

Among 52 neonates in E-SRT group, 13 neonates had died; 12 neonates died within 28 days of life (neonatal death) and 1 died after 28 days (post-neonatal death). Of these 13 neonates, 11 were intubated until death while 2 neonates were extubated but died afterward. There were no significant differences in sex, body type, admission status, BW, GA and doses of SRT between neonates who survived and died. Duration of IMV among neonates who died was significantly shorter than neonates who survived [median 4 (IQR 2,14) days vs. 24 (IQR 6,37) days, difference of medians 16 (95%CI 2-26) days; p = 0.015]. Similarly, duration of oxygen supplement was

TABLE 2. Surfactant, SRT techniques and ventilator characteristics.

Abbreviations: SRT = surfactant replacement therapy, * = statistically significant, P = poractant alfa, P+Bd = poractant alfa and budesonide, B = beractant, B+Bd = beractant and budesonide, ETT-IMV = endotracheal tube with invasive mechanical ventilation technique, INSURE

= intubation-surfactant-extubation technique, LISA = less-invasive surfactant administration technique, † = median and interquartile range,

‡ = mean ± standard deviation, SRT = surfactant replacement therapy, NIV = non-invasive ventilation, HFOV = high-frequency oscillatory ventilation

TABLE 3. Durations of ventilator support and oxygen supplements.

0.239

Duration of oxygen (days) † 44.0 44.0 44.0 -3.0

(12.5,79.5) (6.0,82.5) (24.0,71.0) (-20.0 to 15.0)

0.655

Neonates using oxygen at

53 (74.6) 31 (77.5) 22 (70.9)

1.41

0.586

Neonates using oxygen at

36 weeks (%) †, ‡

43 (60.6)

27 (67.5)

16 (51.6)

1.95

(0.74-5.13)

0.223

28 days (%) †, ‡ (0.48-4.11)

Neonates required home

10 (14.1) 6 (15.0) 4 (12.9)

1.19

0.541

oxygen (%) †, ‡ (0.31-4.65)

Abbreviations: 95%CI = 95% confidence interval, † = median and interquartile range, * = statistically significant, OR = odd ratio, ‡ = only surviving to discharge neonates

also shorter among neonates who died [median 4 (IQR 2,14) days vs. 57 (IQR 28,85) days, difference of medians 49 (95%CI 21-70) days; p < 0.001]. However, duration of NIV was not statistically different. Common causes of death were lung hypoplasia, septicemia and severe IVH. Details about non-surviving neonates were shown in Table 5.

Factors associated with duration of ventilator support and length of stays

Multivariate regression analysis found that factors independently associated with IMV duration were VAP, and septicemia. Neonates who had VAP would have

longer duration of IMV than neonates without VAP with mean increase of 19.8 days (95%CI 11.3-28.3 days; p < 0.001). Similarly, neonates with septicemia would have longer IMV duration with a mean increase of 13.4 days (95%CI 4.4-22.4 days; p = 0.004).

Factors associated with increased duration of NIV were number of SRT dose, and hsPDA. Duration of NIV increased by 19.9 days (95%CI 2.6-37.3 days; p = 0.025) per each SRT dose received while having hsPDA increased NIV duration by 13.1 days (95%CI 1.7-24.5 days; p = 0.025). In contrary, higher BW or GA, and having completed course of antenatal steroid was associated with decreased duration of NIV. Per each 100 grams increased in BW

TABLE 4. Other outcomes.

ROP treatment†

Abbreviations: SRT = surfactant replacement therapy, OR = odd ratio, 95%CI = 95% confidence interval, * = statistically significant, ROP

= retinopathy of prematurity, ‡ = mean ± SD, § = mean difference, † = Excluded neonates who had died before the timing of diagnosis

TABLE 5. Characteristics of non-surviving neonates.

Abbreviations: † = median and interquartile range, * = statistically significant

could reduce NIV duration by 3.2 days (95%CI 1.6-4.8 days; p < 0.001). Similarly, each week increased in GA was associated with a 4.1-day (95%CI 1.4-6.6 days; p = 0.003) reduction in NIV duration. Having completed antenatal corticosteroid could reduce NIV duration by

6.9 days (95%CI 0.5-13.4 days; p = 0.035).

Longer length of stays was associated with number of SRT dose, VAP, septicemia and hsPDA while increased

in GA and BW was associated with shorter length of stays. With each week increased in GA associated with 5.4 days (95%CI 2.7-8.0 days; p <0.001) reduction in length of stays. On the contrary, having septicemia, multiple doses of SRT, VAP, or hsPDA would prolong duration of hospitalization. Factors associated with duration of ventilator support and length of stays were shown in Table 6.

TABLE 6. Factors associated with ventilator support and length of stays.

TABLE 6. Factors associated with ventilator support and length of stays. (Continued)

Abbreviations: IMV = invasive mechanical ventilator, 95%CI = 95% confidence interval, * = statistically significant, SRT = surfactant replacement therapy, NIV = non-invasive mechanical ventilator, PDA = patent ductus arteriosus

DISCUSSION

Several studies showed that E-SRT could benefit neonates with RDS more than L-SRT in shortening the duration of IMV and NIV.4,5 A 2012 Cochrane review also concluded that E-SRT could reduce risk for air leak syndrome, BPD and mortality rate.15 However, this study demonstrated that neonates who received E-SRT had longer duration of IMV than neonates receiving L-SRT although not statistically significant. Similarly, duration of NIV, duration of oxygen usage, oxygen usage at 28 days and oxygen usage at 36 weeks PMA were also longer among neonates in E-SRT group but also not statistically significant. The reason for these conflicting outcomes could be explained by the lower GA and BW and higher rates of hsPDA, septicemia and VAP among neonates in E-SRT group which could be associated with more severe RDS with critically ill conditions prompting immediate intubation and SRT while neonates in L-SRT group could be more medically stable and received SRT later when RDS had progressed. Clinical severity of neonates in E-SRT group could be

noted with more neonates received multiple doses of SRT than neonates in L-SRT group. Likewise, this also reflected in the significantly lower number of neonates in E-SRT group with IMV-free, NIV-free, and oxygen- free days at age of 60 days than L-SRT group.

This study found that factors independently associated with longer duration of respiratory support were having VAP, and septicemia. VAP is a common complication among preterm neonates causing inflammation and injury to the lungs while septicemia causes systemic inflammatory response syndrome leading to inflammatory lung injury. Additionally, neonates with VAP and septicemia are likely to be medically unstable requiring prolonged IMV support which could directly injure the lungs by volutrauma and barotrauma leading to BPD.16,17 Multiple doses of SRT was shown to help reducing mortality and respiratory supports among neonates with severe RDS.18 In this study, most of neonates who received multiple doses of SRT were in E-SRT group who had lower GA and BW and could possibly have more severe RDS leading to the requirement of multiple doses of SRT.

These neonates could have other pathogenic mechanisms, such as infection, causing surfactant inactivation and, therefore, requiring subsequent SRT.19 This study also found that neonates in E-SRT group had higher rate of VAP and septicemia which could better explain the longer duration of IMV support rather than by having multiple doses of SRT.

In terms of NIV, multiple factors were associated with longer duration of NIV support such as number of SRT dose and hsPDA similar to previous studies that demonstrated hsPDA could contribute to longer duration of IMV, NIV and oxygen supplements.20,21 Higher number of SRT dose was associated with more severe RDS which could also lead to longer duration of IMV, NIV, length of stays. Although length of stays did not differ significantly between each group, factors that could prolonged hospitalization were VAP, septicemia, and hsPDA according to this study.

After adjusted for sex, GA and BW, there was no significant differences about IVH, air leak syndrome, hsPDA, septicemia, VAP, NEC, and BPD between neonates in E-SRT and L-SRT groups which mean that timing of SRT was not associated with adverse outcomes. Neonates in E-SRT group also had significantly more IMV support before SRT than L-SRT group. It is known that IMV is associated with lung injury due to volutrauma and barotrauma leading to BPD. At our institution, pressure- controlled with volume guarantee (VG) for conventional IMV and HFOV with VG were used in all neonates who were intubated to minimized fluctuation of tidal volume, and thus, minimizing volutrauma effect from IMV. This could explain the BPD rate among neonates in both group which did not differ significantly. However, ROP rate was higher among neonates in E-SRT group which could be caused by the longer duration of IMV, NIV and oxygen supplement.

Another finding from this study was the mortality rate which was significantly higher among neonates in E-SRT group. However, causes of death were not related to RDS i.e., lung hypoplasia, severe IVH and septicemia, which were mainly associated with prematurity and was not treatable with SRT. There were no significant differences in characteristics of neonates in E-SRT group who survived or died in terms of sex, GA and BW.

This study demonstrated that VAP and septicemia were important risk factors that could prolong duration of IMV while timing of SRT did not show to be associated with. Additionally, VAP and septicemia were also associated with longer length of stays. Strict protocol to prevent VAP and septicemia should be implemented to help shorten the need for ventilator support and hospital stays.

Additionally, this study found that timing of SRT did not associate with prolonged duration of ventilator support or other adverse outcomes. Therefore, in resource-limited settings it would be logical to wait and selectively provide SRT to neonates who are in need of the treatment to maximize SRT effectiveness and to avoid unnecessary SRT with less concern for adverse outcomes. Treating hsPDA may also reduce duration of NIV and length of stays.

Limitations

Several limitations were noted in this study. The number of neonates receiving SRT was relatively small and the design of the study was retrospective, therefore, the results might be affected by confounding factors. There were no standard criteria for SRT or extubation causing treatment variation among neonates. Surfactant types and doses were also varied among neonates. Recommended dose for poractant alfa was 200 mg/kg and for beractant was 100 mg/kg but due to cost constrain, majority of neonates had received lower dose than the recommendation. A prospective randomized control trial study with larger population and standard criteria for SRT, dosage of surfactant and extubation criteria could provide more accurate results.

CONCLUSION

Neonates who received E-SRT had longer duration of IMV than neonates who received L-SRT but not statistically significant. Also, there were no significant differences in other neonatal outcomes between each group. Adverse outcomes were likely to be related to GA and BW rather than timing of SRT. VAP and septicemia were major factors associated with prolonged ventilator support and adverse neonatal outcomes, thus, emphasis on preventing VAP and septicemia could be beneficial for neonates.

ACKNOWLEDGEMENTS

We would like to acknowledge Mr.Gurdeep Singh for editing the manuscript via Publication Clinic KKU, Thailand.

Conflicts of interest statement

Authors had no conflict of interest to declare.

REFERENCES

1. Ainsworth SB. Pathophysiology of Neonatal Respiratory Distress Syndrome. Treat Respir Med. 2005;4(6):423-37.

2. Jobe AH. 158 - Pathophysiology of Respiratory Distress Syndrome. In: Polin RA, Abman SH, Rowitch DH, Benitz WE, Fox WW,

   
   

   editors. Fetal and Neonatal Physiology (Fifth Edition): Elsevier; 2017.p.1604-19.e2.

3. Kirsten GF, Kirsten CL, Henning PA, Smith J, Holgate SL, Bekker A, et al. The Outcome of ELBW Infants Treated With NCPAP and InSurE in a Resource-Limited Institution. Pediatrics. 2012;129(4):e952-e9.

4. Kandraju H, Murki S, Subramanian S, Gaddam P, Deorari A, Kumar P. Early routine versus late selective surfactant in preterm neonates with respiratory distress syndrome on nasal continuous positive airway pressure: a randomized controlled trial. Neonatology. 2013;103(2):148-54.

5. Kim SM, Park YJ, Chung SH, Choi YS, Kim CH, Bae CW. Early prophylactic versus late selective use of surfactant for respiratory distress syndrome in very preterm infants: a collaborative study of 53 multi-center trials in Korea. J Korean Med Sci. 2014;29(8): 1126-31.

6. Rebello CM, Nacif LF, Deutsch AD, Paes AT. Timing of initial surfactant treatment in very low birth weight newborns. Einstein (Sao Paulo). 2010;8(3):320-4.

7. Verder H, Robertson B, Greisen G, Ebbesen F, Albertsen P, Lundstrøm K, et al. Surfactant therapy and nasal continuous positive airway pressure for newborns with respiratory distress syndrome. Danish-Swedish Multicenter Study Group. N Engl J Med. 1994;331(16):1051-5.

8. Kribs A, Roll C, Göpel W, Wieg C, Groneck P, Laux R, et al. Nonintubated Surfactant Application vs Conventional Therapy in Extremely Preterm Infants: A Randomized Clinical Trial. JAMA Pediatr. 2015;169(8):723-30.

9. Bancalari E, del Moral T. Bronchopulmonary Dysplasia and Surfactant. Neonatology. 2001;80(Suppl. 1):7-13.

10. Polin RA, Carlo WA. Surfactant replacement therapy for preterm and term neonates with respiratory distress. Pediatrics. 2014;133(1):156-63.

11. Ng EH, Shah V. Guidelines for surfactant replacement therapy in neonates. Paediatr Child Health. 2021;26(1):35-49.

12. Yeh TF, Lin HC, Chang CH, Wu TS, Su BH, Li TC, et al. Early intratracheal instillation of budesonide using surfactant as a vehicle to prevent chronic lung disease in preterm infants: a pilot study. Pediatrics. 2008;121(5):e1310-8.

13. Yeh TF, Chen CM, Wu SY, Husan Z, Li TC, Hsieh WS, et al. Intratracheal Administration of Budesonide/Surfactant to Prevent Bronchopulmonary Dysplasia. Am J Respir Crit Care Med. 2016;193(1):86-95.

14. Higgins RD, Jobe AH, Koso-Thomas M, Bancalari E, Viscardi RM, Hartert TV, et al. Bronchopulmonary Dysplasia: Executive Summary of a Workshop. J Pediatr. 2018;197:300-8.

15. Bahadue FL, Soll R. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database Syst Rev. 2012;11(11):CD001456.

16. Cernada M, Brugada M, Golombek S, Vento M. Ventilator- Associated Pneumonia in Neonatal Patients: An Update. Neonatology. 2014;105(2):98-107.

17. Balany J, Bhandari V. Understanding the Impact of Infection, Inflammation, and Their Persistence in the Pathogenesis of Bronchopulmonary Dysplasia. Front Med (Lausanne). 2015;2:90.

18. Soll R, Ozek E. Multiple versus single doses of exogenous surfactant for the prevention or treatment of neonatal respiratory distress syndrome. Cochrane Database Syst Rev. 2009;(1):CD000141.

19. Tsakalidis C, Giougki E, Karagianni P, Dokos C, Rallis D, Nikolaidis N. Is there a necessity for multiple doses of surfactant for respiratory distress syndrome of premature infants? Turk J Pediatr. 2012;54(4):368-75.

20. Willis KA, Weems MF. Hemodynamically significant patent ductus arteriosus and the development of bronchopulmonary dysplasia. Congenit Heart Dis. 2019;14(1):27-32.

21. Potsiurko S, Dobryanskyy D, Sekretar L. Patent ductus arteriosus, systemic NT-proBNP concentrations and development of bronchopulmonary dysplasia in very preterm infants: retrospective data analysis from a randomized controlled trial. BMC Pediatrics. 2021;21(1):286.

Transvaginal Urethrolysis as a Treatment Option for Women with Recurrent Cystitis

Sunporn Boonwong, M.D.*, Atichet Sawangchareon, M.D.**, Patkawat Ramart, M.D.*

*Division of Urology, Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand, **Division of Urology, Department of Surgery, Taksin Hospital, Medical Service Department, Bangkok Metropolitan Administration, Bangkok, 10600, Thailand.

ABSTRACT

Objective: To demonstrate the outcome of transvaginal urethrolysis as a treatment option for women with recurrent cystitis, which could be caused from voiding problems. In the case of a failure of non-invasive treatment, the surgical procedure to decrease outlet resistance may have a role.

Materials and Methods: Between January 2016 and December 2020, women with recurrent cystitis who underwent urethrolysis at Siriraj Hospital were retrospectively reviewed. Only women who were followed-up for more than 6 months were analyzed. Cure was defined by no clinical symptoms of cystitis, no pyuria on urine analysis, and/or negative urine culture during the follow-up period.

Results: In total, 52 women underwent transvaginal urethrolysis. The overall cure rate was observed 53.9% (28 cases) at a median follow-up time of 11.9 (6–59) months. Eighteen of the 44 cases (40.9%) who underwent a video urodynamics study showed bladder outlet obstruction, defined as a Solomon–Greenwell bladder outlet obstruction index of more than 5. None of the characteristics or urodynamics parameters showed statistically significant differences between the cure and failure groups. Postoperative urinary incontinence was reported in 14 cases (26.9%) but showed no statistical difference between the cure and failure group (p = 0.748).

Conclusion: Bladder outlet obstruction is a common cause of recurrent cystitis. Transvaginal urethrolysis may have a role as treatment for women with recurrent cystitis from voiding dysfunction who have failed non- and less-invasive treatments. Here, the overall cure rate was 53.8%. A factor associated with the cure rate could not be demonstrated in this study.

Keywords: Recurrent cystitis; voiding dysfunction; bladder outlet obstruction; detrusor underactivity; urethrolysis (Siriraj Med J 2023; 75: 343-349)

INTRODUCTION

Cystitis is an inflammation of the urinary bladder and presents with dysuria in conjunction with urinary frequency, urgency, hematuria, worsening urinary incontinence, or suprapubic pain1, and is usually associated with infection. The incidence of cystitis is significantly higher in women as a result of lower urinary tract anatomy. A study into the self-reported incidence of urinary tract

infection (UTI) showed that 10.8% of women aged 18 years old or older have reported at least one presumed UTI during the past 12 months and estimated that 60.4% of all women experience at least one episode of UTI in a lifetime.2 A study of community-acquired Escherichia coli cystitis reported that 49.2% of female patients had at least one episode of recurrent urinary tract infection (UTI) during 12-month follow-up and most of them

Corresponding author: Patkawat Ramart E-mail: patkawat.ram@mahidol.ac.th

Received 15 February 2023 Revised 10 March 2023 Accepted 11 March 2023 ORCID ID:http://orcid.org/0000-0002-3394-9349 https://doi.org/10.33192/smj.v75i5.261230

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

were recurrent cystitis.3 After the first episode of cystitis in young women, the 6-month risk of second UTI was reported to be 26.6%.4 Moreover, genitourinary tract infection was found to be the second most common infection in a geriatric population.5

Complicated UTI, including recurrent infection, and urinary tract infection in an immunocompromised host, and/or with multi-drug resistant bacteria and in patients with a suspected anatomical or functional abnormality of the urinary tract, should be investigated.1 Therefore, recurrent cystitis is considered an unusual problem, particularly from bacterial infection. The widely accepted definition of recurrent cystitis is described as 3 or more episodes of cystitis confirmed by a positive urine culture during a previous 12-month period or 2 or more episodes of infection during a 6-month period.1 Bladder outlet obstruction (BOO) is another cause

of recurrent cystitis, so the concept of reducing outlet resistance to treat women with recurrent cystitis was proposed and studied in the past.6-8 Treatment options include biofeedback9, alpha-adrenergic antagonist9, urethral dilation, internal urethrotomy6,7, and urethrolysis.8 Specifically, urethrolysis is an outlet reducing procedure that is used to treat female urethral syndrome8 and bladder outlet obstruction after anti-incontinence procedures.10,11 The procedure can be performed by a transvaginal, suprameatal, or retropubic approach.

The majority of studies have demonstrated that urethrolysis is an effective treatment for bladder outlet obstruction after anti-incontinence procedures and the success rate is between 58%–87%.11-14 So far, to the best of our knowledge, there has been only one study on urethrolysis as a treatment in women with recurrent cystitis8, but the surgical technique reported was different from in other studies. Therefore, this study aimed to demonstrate the outcome and role of transvaginal urethrolysis considering the same surgical techniques as other studies11-13, more specifically for the case of lower urinary tract abnormality, which is a cause of recurrent cystitis. The second aim was to identify the predictive factors that might affect the outcome of urethrolysis.

MATERIALS AND METHODS

After the study was approved by the institutional review board, the medical records of all female patients who underwent urethrolysis between January 2016 and December 2020 at Siriraj Hospital were retrospectively reviewed. Only patients who had a history of recurrent cystitis and who were followed up at least 6 months after urethrolysis were enrolled and analyzed. Most cases had failed non- and less-invasive treatment, including

alpha-adrenergic antagonist and urethral dilation, before it was decided to perform urethrolysis.

Patients who had a history of pelvic radiation, neurologic diseases with a significant abnormal neurologic examination, abnormal urinary tract findings on imaging studies, pelvic organ prolapse more than stage I on vaginal examination, and a history of past urethrolysis were excluded. Information from the medical records, including age, voiding symptoms, parity, history of vaginal surgery, diabetes mellitus, findings on vaginal examination, video urodynamics (VUDS) report, and outcome during the follow-up period were collected.

Recurrent cystitis was defined by 3 or more occurrences of clinical symptoms, including dysuria, frequency, and urgency, as well as demonstrated pyuria (White blood cells > 5 per high power field) on urine analysis (UA) and a positive urine culture for bacteria in the past year. All the cases must have failed to respond to proper antibiotics and subsequent medications, including alpha-adrenergic antagonists, bethanechol chloride, or vaginal estrogen, for at least 3 months.

To identify a cause of recurrent cystitis, careful history taking, vaginal examination, and/or video urodynamics study (VUDS) were performed. Vaginal examination indicated a loss of urethral mobility, and fixed and over- angulated urethra in all cases. If the clinical history indicated that BOO was strongly related to a past vaginal surgery, and/or vaginal examination revealed a mesh extrusion, VUDS was omitted. VUDS was performed in a sitting position on a radiolucent commode chair. The bladder outlet obstruction index for females (BOOIf), known as the Solomon–Greenwell formula, was used as a diagnostic criterion.15 If BOOIf was more than 5, the patient was diagnosed as BOO.

During pressure-flow studies (PFS), if a patient was unable to void with a urethral catheter in place, the catheter would be removed, and then the patient would attempt to void with the rectal catheter in place to measure abdominal pressure, and fluoroscopy was utilized to demonstrate the urethral anatomy. Abnormal urethral findings on the fluoroscopic examination, including distortion or disproportion, were reported (Fig 1). In cases of unsuccessfully performed PFS both with and without the urethral catheter, free uroflowmetry and post- void residual urine tests were performed and measured in a private room, and these patients were diagnosed as non-specific voiding dysfunction (NVD). All the NVD showed a loss of urethral mobility and over-angulated urethra, as well as maximal urinary flow rate (Qmax), which was less than 20 ml/sec.

To demonstrate the outcome of urethrolysis in

Fig 1. Fluoroscopic picture in a woman with recurrent cystitis demonstrated disproportion of the urethra (arrow) during a pressure- flow study.

the different types, they were categorized as clinical voiding dysfunction (CVD) and urodynamic bladder outlet obstruction (UBO). Clinical voiding dysfunction (CVD) included bladder outlet obstruction related to a past vaginal surgery, vaginal mesh extrusion, abnormal urethral findings on fluoroscopic examination, BOOIf

≤ 5 in the pressure-flow study or non-specific voiding dysfunction (NVD), while urodynamic bladder outlet obstruction (UBO) was only indicated in a case with a successfully performed pressure-flow study and BOOIf of more than 5.

For the outcome of urethrolysis, in order to make clear on the definition of cure, it was defined by no clinical symptoms and no pyuria on urine analysis during the follow-up period. Because asymptomatic bacteriuria might sometimes develop clinically significant cystitis which patients did not receive an appropriate investigation and took antibiotic by their own. In contrast, failure was defined as recurrent clinical symptoms of cystitis and demonstrated pyuria on urine analysis or a positive urine culture during the follow-up period.

Surgical technique

For transvaginal urethrolysis, a patient was positioned in the exaggerated dorsal lithotomy, and the operation was performed under general anesthesia. After the urethral catheter was indwelled and the bladder was emptied, the vagina was examined. Urethral mobility was evaluated by pulling the catheter. Bilateral incisions were made at the anterior vaginal wall, along the paraurethral area. The vaginal wall was dissected until the pubocervical fascia was identified. The fascia was punctured and disintegrated by curved-Mayo scissors and then the prevesical space was entered. In order to avoid bladder

perforation, the bladder must be emptied before puncture and the curved-Mayo scissors must be pointed laterally, close to the pubic rami. Paraurethral tissue was bluntly dissected by the index finger while the paraurethral area and prevesical space were also freed up. In the case of synthetic mesh implantation, nearly the entire mesh was removed. The urethral mobility was re-evaluated by pulling the urethral catheter and by observing an increasingly downward movement of the urethra compared to preoperative evaluation. Bleeding was checked and secured. Vaginal incisions were properly re-approximated with non-absorbable sutures without intentional overbite stitches to avoid further scarring, potentially leading to a urethral obstruction. Vaginal packing with betadine- soaked gauze was kept in place for 24 hours. At 24-hour postoperative, the vaginal packing and urethral catheter were removed and the patient was discharged.

Statistical analysis

Descriptive statistics regarding age, diabetes mellitus, and past vaginal surgery were reported using the quantity as a number and percentage. Each of the video urodynamics parameters, including maximal urinary flow rate (Qmax), detrusor pressure at a maximal flow rate (PdetQmax), voided volume (VV), and post-void residual (PVR), were reported as the median with the minimum and maximum value according to the normal distribution. To analyze the factors implicating the urethrolysis outcome, qualitative factors, including the voiding symptoms, diabetes mellitus (DM), and past vaginal surgery, were compared by using the Chi-square test and Fisher’s exact test. While the quantitative data, including age, Qmax, PdetQmax, and other urodynamics parameters, were compared by the unpaired t-test and Mann–Whitney U-test and reported as the mean or median between these two groups. All the data were analyzed using the program SPSS Inc., released in 2009, PASW Statistics for Windows, Version 18.0. Chicago: SPSS Inc. These analyses used a 2-tailed test and considered statistically significant when p < 0.05.

RESULTS

A total of 127 cases who underwent urethrolysis during 5 years in our institute were reviewed and 7 cases were excluded because of a history of pelvic radiation. Only 52 cases met the inclusion criteria. The mean age was 68.8 ± 12.5 years old and 18 cases (34.6%) complained of voiding symptoms. Diabetes mellitus (DM) was found for 16 cases (30.8%) and the median parity was 3 (0–10). Twenty-four cases (46.2%) had a history of past vaginal surgery, including pelvic organ prolapse

procedures (9 cases), anti-incontinence procedures (8 cases), and combined prolapse organ prolapse with anti- incontinence procedures (5 cases). In these groups, 5 cases had bladder outlet obstruction strongly related to vaginal surgery and 3 cases had vaginal mesh extrusion, so they underwent transvaginal urethrolysis without preoperative video urodynamics study (VUDS). The remaining 44 cases had VUDS performed, including 30 cases (68.2%) with a successful pressure-flow study (PFS) and 14 cases (31.8%) with an unsuccessful PFS, which were categorized as non-specific voiding dysfunction (NVD). In the successful PFS, BOO, which was named as urodynamic bladder outlet obstruction (UBO), and non-bladder outlet obstruction were diagnosed in 18 and 12 cases, respectively. In addition, 28 of the 44 cases (63.3%) who had VUDS performed showed an abnormal urethra on fluoroscopic examination. To easily apply clinical practice, 34 cases were categorized as clinical voiding dysfunction (CVD), and 18 cases were also categorized as urodynamic bladder outlet obstruction (UBO) (Table 1).

Overall, the cure rate was observed as 53.8% (28 cases) and the median follow-up time was 11.9 (6–59) months. The cure rates between CVD and UBO were 55.9% and 50.9%, respectively, and there was no statistically significant difference between the two groups (p = 0.91). The predictive factors associated with the cure rate were analyzed but no characteristics showed a statistically significant difference (Table 2). In a subgroup analysis of UBO, there was no significant urodynamic parameters associated with the cure rate (Table 3).

There was no intraoperative bladder or urethral injury. One case required postoperative blood transfusion without any further intervention and one case had vaginal infection, which was successfully treated with oral antibiotics. During follow-up, 14 cases (26.9%) reported urinary incontinence (UI), among whom 8 had only mild symptoms, using only 1 protective pad per day, while 5 cases had severe urinary incontinence. Among the severe urinary incontinence cases, 3 were requested and scheduled for anti-incontinence procedures. The urinary incontinence rate was not statistically significant difference between the cure and failure group (p = 0.748). Interestingly, 8 of the 14 cases did not have recurrent cystitis during the follow-up period. Five cases (9.6%) that reported overactive bladder after urethrolysis required medical treatment. Four cases of the failure group underwent repeated urethrolysis because their clinical cystitis was improved during the initial 6 months of the postoperative period and voiding dysfunction was confirmed. Two cases still had recurrent cystitis postoperatively and

the remaining complained of urinary incontinence and voiding symptoms without recurrent cystitis.

DISCUSSION

Recurrent cystitis in women is considered a complicated urinary tract infection (UTI) and an unusual problem. The AUA/CUA/SUFU guideline suggests complicated UTI should be investigated to identify a possible anatomical and functional abnormality.1 Recurrent cystitis is another presentation of voiding problems, especially bladder outlet obstruction (BOO) after anti-incontinence procedures12,16, even though, the majority of cases present with storage symptoms or combined storage and voiding symptoms rather than voiding symptoms alone.8,10-12

When focusing on the treatment of recurrent cystitis from voiding problems, some cases have mixed functional and anatomical problems. Therefore, all the cases in this study had been initially treated with an alpha-adrenergic antagonist with an aim to theoretically reduce outlet resistance, but they still had recurrent episodes of cystitis. For anatomical BOO without pelvic organ prolapse, the treatment options are urethral dilation, urethrotomy, urethrolysis, and urethroplasty.17

In the past studies, the improvement rate was 80%– 100% of women with recurrent cystitis who were treated with urethral dilation using a sound dilator up to 40–45 Fr., but it needed repeat dilation.18-19 In the present study, the majority of cases had been treated with urethral dilation with Hegar dilators, but they were not improved, and then they accepted the risk from urethrolysis after counseling. Moreover, 28 cases had abnormal urethral findings on fluoroscopic examination, which confirmed that the urethral narrowing or distortion was from outside of the lumen, named “periurethral fibrosis”. Because of this reason, urethrotomy was not considered in this study, even though urethrotomy followed by urethral dilation up to 40–46 Fr. has shown excellent results in 31%–52% of cases.6,20

Most studies demonstrated that urethrolysis was an effective treatment for BOO after an anti-incontinence procedure and the success rate was 58%–87%.11-14 There was only one study of urethrolysis used for treating 40 women with recurrent frequency and dysuria demonstrated who failed medical treatment and urethral dilation, and showed that 18 of the 40 women (45.0%) reported good results at a mean follow-up time of 10.7 (range 4–36) months. Only one woman who had recurrent frequency and dysuria with recurrent UTI reported poor results that were unsatisfactory, but urethrolysis was performed using a different technique, described as releasing the posterior support along the urethra. Two cases had stress

TABLE 1. Demographic data of all the cases.

† BOO or bladder outlet obstruction.

‡ VUDS or video urodynamics study.

§ NVD or non-specific voiding dysfunction was defined as a loss of urethral mobility and overangulated urethra on vaginal examination and a maximal urinary flow rate (Qmax) < 20 ml/sec on free uroflowmetry and an unsuccessful pressure-flow study with and without a urethral catheter.

¶ BOOIf or bladder outlet obstruction index for female defined by Solomon–Greenwell.

†† UBO or urodynamic bladder outlet obstruction was indicated in successful PFS and BOOIf > 5.

‡‡ Qmax or maximal urinary flow rate.

§§ PdetQmax or detrusor pressure at the maximal urinary flow rate.

urinary incontinence after urethrolysis.8 In our study, the overall cure rate, defined by no clinical symptoms and no pyuria on urinalysis during the follow-up period, was 53.8%.

Some studies mentioned that urethrolysis may be reasonable for clinical BOO without urodynamic

proof by using a history of vaginal surgery, fixed or hypersuspended urethra on physical examination, or trabeculation on cystoscopy.12,13 The outcomes were similar between clearly defined urodynamic BOO and the inability to generate detrusor contraction on the UDS.12 This study also demonstrated that both CVD and UBO

Treatment outcome

Characteristics

Total

(n = 52)

Cure

(n = 28)

Failure

(n = 24)

P-value

TABLE 2. Characteristics associated with the cure rate.

TABLE 3. Subgroup analysis of the pressure-flow study parameters in urodynamic bladder outlet obstruction (UBO).

† Qmax or maximal urinary flow rate.

‡ PdetQmax or detrusor pressure at the maximal urinary flow rate.

§ BOOIf or bladder outlet obstruction index for females defined by Solomon–Greenwell.

had the same cure rate. It is a matter of fact that the female lower urinary tract anatomy and function is unreliable, and so it is difficult to initiate the most appropriate criteria for bladder outlet obstruction upon urodynamics study as in males.21 So, clinical information, including the patient’s history and precise vaginal examination, may be an important key. Unfortunately, the present study could not demonstrate any factor associated with the cure rate.

Previous studies have reported various postoperative urinary incontinence rates, ranging from 0% to 38.9%11-13,22,

depending on the population and surgical technique. The postoperative urinary incontinence rate in our study was 26.9%. Postoperative overactive bladder (OAB) is another problem that impacts the quality of life and individual satisfaction.12,23 About 50% of cases had OAB symptoms after urethrolysis, and preoperative overactive bladder and/or detrusor overactivity (DO) are indicators of poor postoperative satisfaction.23 Our study showed that 9.6% of cases had OAB symptoms that required medical treatment. Interestingly, postoperative OAB in our study was low because if our patients had both

OAB symptoms and recurrent cystitis, they were not diagnosed as OAB. Moreover, the repeat urethrolysis rate was widely different from that in past studies because of the different indications and diagnoses. In our study, only 4 cases were classified as failed urethrolysis at more than 6 months postoperatively; however, they had some symptoms improvement. After re-evaluation, they agreed to repeat urethrolysis.

The strengths of this study include that we studied in more specific conditions voiding dysfunction causing recurrent cystitis, and the surgical procedure was performed by a single surgeon with the same surgical technique, and also that no previous urethrolysis was performed in the cohort population. The limitations were the retrospective design of this study, which meant there were some missing data and only a small number of enrolled cases.

In conclusion, after the failure of non- and less- invasive treatments, urethrolysis may be a treatment option for women with recurrent cystitis from voiding problems. The overall cure rate was 53.8% in this study. Either clinical or urodynamic bladder outlet obstruction can be used as an indication for urethrolysis and here showed a comparable cure rate. No factor associated with the cure rate was demonstrated.

REFERENCES

1. Anger J, Lee U, Ackerman AL, Chou R, Chughtai B, Clemens JQ, et al. Recurrent Uncomplicated Urinary Tract Infections in Women: AUA/CUA/SUFU Guideline. J Urol 2019;202(2): 282-9.

2. Foxman B, Barlow R, D’Arcy H, Gillespie B, Sobel JD. Urinary tract infection: self-reported incidence and associated costs. Ann Epidemiol 2000;10(8):509-15.

3. Ikaheimo R, Siitonen A, Heiskanen T, Karkkainen U, Kuosmanen P, Lipponen P, et al., Recurrence of urinary tract infection in a primary care setting: analysis of a 1-year follow-up of 179 women. Clin Infect Dis 1996;22(1):91-9.

4. Foxman B. Recurring urinary tract infection: incidence and risk factors. Am J Public Health 1990;80(3):331-3.

5. Ruben FL, Dearwater SR, Norden CW, Kuller LH, Gartner K, Shalley A, et al., Clinical infections in the noninstitutionalized geriatric age group: methods utilized and incidence of infections. The Pittsburgh Good Health Study. Am J Epidemiol 1995;141(2): 145-57.

6. Farrar DJ, Green NA, Ashken MH. An evaluation of Otis urethrotomy in female patients with recurrent urinary tract infections. Br J Urol 1973;45(6):610-5.

7. Keitzer WA, Allen JS. Operative treatment of chronic cystitis by urethrotomy: 10 years of experience. J Urol 1970;103(4): 429-31.

8. Smith PJ, Powell PH, George NJ, Kirk D. Urethrolysis in the

   management of females with recurrent frequency and dysuria. Br J Urol 1981;53(6):634-6.

9. Minardi D, Pellegrinelli F, Conti A, Fontana D, Mattia M, Milanese G, et al. alpha1-Blockers for the treatment of recurrent urinary tract infections in women with dysfunctional voiding: a prospective randomized study. Int J Urol 2015;22(1):115-21.

10. Nitti VW, Raz S. Obstruction following anti-incontinence procedures: diagnosis and treatment with transvaginal urethrolysis. J Urol 1994;152(1):93-8.

11. McCrery R, Appell R. Transvaginal urethrolysis for obstruction after antiincontinence surgery. Int Urogynecol J Pelvic Floor Dysfunct 2007;18(6):627-33.

12. Foster HE, McGuire EJ. Management of urethral obstruction with transvaginal urethrolysis. J Urol 1993;150(5 Pt 1):1448-51.

13. Carr LK, Webster GD. Voiding dysfunction following incontinence surgery: diagnosis and treatment with retropubic or vaginal urethrolysis. J Urol 1997;157(3):821-3.

14. Goldman HB, Rackley RR, Appell RA. The efficacy of urethrolysis without re-suspension for iatrogenic urethral obstruction. J Urol 1999;161(1):196-8; discussion 198-9.

15. Solomon E, Yasmin H, Duffy M, Rashid T, Akinluyi E, Greenwell TJ. Developing and validating a new nomogram for diagnosing bladder outlet obstruction in women. Neurourol Urodyn 2018; 37(1):368-78.

16. Woodman PJ, Ruiz HL. Retropubic urethrolysis without resuspension for the management of posturethropexy urinary retention and voiding dysfunction. Mil Med 2004;169(2):117- 20.

17. Meier K, and Padmanabhan P. Female bladder outlet obstruction: an update on diagnosis and management. Curr Opin Urol 2016; 26(4):334-41.

18. Essenhigh DM, Ardran GM, Cope V. A study of the bladder outlet in lower urinary tract infections in women. Br J Urol 1968;40(3): 268-77.

19. McCannel DA, Haile W. Urethral narrowing and its treatment: a possible solution for the problems of recurrent urinary infection and the “irritable bladder”. Int Urol Nephrol 1982;14(4):407- 14.

20. Immergut MA, Gilbert EC. The clinical response of women to internal urethrotomy. J Urol 1973;109(1):90-1.

21. Pang KH, Campi R, Arlandis S, Bo K, Chapple CR, Costantini E, et al., Diagnostic Tests for Female Bladder Outlet Obstruction: A Systematic Review from the European Association of Urology Non-neurogenic Female LUTS Guidelines Panel. Eur Urol Focus 2022;8(4):1015-30.

22. Giannis G, Bousouni E, Mueller MD, Imboden S, Mohr S, Raio L, et al. Can urethrolysis resolve outlet obstruction related symptoms after Burch colposuspension for stress urinary incontinence? Eur J Obstet Gynecol Reprod Biol 2015;195: 103-7.

23. Starkman JS, Duffy JW 3rd, Wolter CE, Kaufman MR, Scarpero HM, Dmochowski RR. The evolution of obstruction induced overactive bladder symptoms following urethrolysis for female bladder outlet obstruction. J Urol 2008;179(3):1018-23.

The Relationship between Kolb Learning Style and Academic Performances in Orthopedic Residents

Cherdsak Iramaneerat, M.D., Ph.D.*,**, Surin Thanapipatsiri, M.D.***, Thasaneeya Ratanaroutai Nopparatjamjomras, Ph.D.**, Thos Harnroongroj, M.D., M.Sc.***

*Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, **Siriraj Health Science Education Excellence Center, Faculty of Medicine Siriraj Hospital, ***Department of Orthopedic Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.

ABSTRACT

Objective: The assimilating and converging Kolb learning style were reported to have positive correlation with critical thinking ability in Orthopedic resident. However, the relationship between Kolb learning styles and academic performance remained controversy. The objective of this study is to report the relationship between Kolb learning style and academic performance in Orthopedic residents.

Materials and Methods: The causal comparative cross-sectional study on 48 Orthopedic residents of academic year 2020 was conducted. The demographic characteristics of the participants were reviewed. The scores from the multiple choices question (MCQ) in-training examination, the objective structured clinical examination (OSCE) and the global performance rating scale were collected to represent academic performances of each Miller’s pyramid of assessment level. The Kolb learning style inventory were allocated. The statistical analysis was performed and p < 0.05 was considered statistically significant difference.

Results: The response rate was 100%. There was no statistically significant difference of MCQ in-training examination, OSCE and global performance rating scale among each learning style as p=0.789, 0.493 and 0.407, respectively. The assimilating and converging styles were the 2 learning styles which had the academic performance scores above the average scores in all assessments.

Conclusion: This study could not demonstrate the significant difference of academic performances among Kolb learning style in Orthopedic residents. However, the assimilating and converging style had the consistent scores above average scores in all domains. The Orthopedic learning experience should focus on the development of reflective observation, abstract conceptualization and active experimentation to facilitate effective improvement in academic performance of the residents.

Keywords: Kolb learning styles; Orthopedic residents; academic performance (Siriraj Med J 2023; 75: 350-355)

INTRODUCTION

Orthopedic resident training requires the development of knowledge, skill and attitude in the limited 4-year time frame.1 Effective experiential learning principle has been proved as an important learning process to enhance the competency development and improve critical

thinking skill in Orthopedic resident.2 The commonly used experiential learning in Orthopedic training is “Kolb learning cycle” which is compose of 4 sequential learning processes as concrete experience, reflective observation, abstract conceptualization and active experimentation (Fig 1).2-5

Corresponding author: Thos Harnroongroj E-mail: harnroongrojt@gmail.com

Received 9 February 2023 Revised 8 March 2023 Accepted 12 March 2023 ORCID ID:http://orcid.org/0000-0003-3330-6869 https://doi.org/10.33192/smj.v75i5.261255

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

Fig 1. The Kolb experiential learning cycle which was composed of 4 sequential learning steps as concrete experience, reflective observation, abstract conceptualization and active experimentation.

According to the “Kolb learning cycle”, the learners could be divided into 4 different “Kolb learning styles” depended on the 2 commonly used learning processes as diverging (concrete experience-reflective observation), assimilating (reflective observation-abstract conceptualization), converging (abstract conceptualization- active experimentation), and accommodating (active experimentation-concrete experience).6 Previous studies found that the 2 commonest Kolb learning styles in Orthopedic residents were mixed between converging (25.0%

- 53.5%), assimilating (9.9% - 37.5 %) and accommodating (18.3% - 22.9%).1,2 And, converging and assimilating was associated with good critical thinking ability as these 2 learning styles used abstract conceptualization as an important process of deep learning strategy.2 Despite those mentioned studies, none had demonstrated the significant relationship between the Kolb learning styles and academic performance in Orthopedic resident.

The objective of this study is to find out the relationship between Kolb learning style and academic performance in Orthopedic resident. The hypothesis in this study is converging and assimilating style which has positive relationship with critical thinking ability2 will have positive relationship with the good academic performance.

MATERIALS AND METHODS

The design of this study was causal comparative cross-sectional study. The study was conducted under the approval of the institutional review board (COA no. Si 010/2021). The Orthopedic residents during academic year 2020 of single institute were included. And, the resident who did not desire to reveal the demographic or educational data as well as unwilled to do the questionnaire was excluded. Finally, there were 48 participants enrolled in this study without excluded sample.

The demographic profile of the participants were reviewed which included sex, age, the graduated medical school and the grade point average of graduated medicine degree. The 5-level Likert scale type native language

Kolb learning style inventory version 3.1 which was consisted of 48 learning habit phrases representing 4 different Kolb learning processes (concrete experience, reflective observation, abstract conceptualization and active experimentation) were allocated to participants to evaluate the Kolb learning style individually.6 The consideration of Kolb learning style was categorized using cartesian graph by calculating of the score of concrete experience minus abstract conceptualization and reflective observation minus active experimentation (Fig 2). The content validity and internal consistency reliability of this questionnaire was acceptable with the Cronbach alpha co-efficient of 0.93.6,7 The questionnaires were collected and analyzed by one well-trained author at the mid-academic year.

Fig 2. The Kolb learning style categorization was based on the calculation using cartesian graph. The vertical line (y axis) was the absolute score of concrete experience minus to abstract conceptualization (CE - AC). The horizontal line (x axis) was the absolute score of reflective observation minus active experimentation (RO - AE). The final plot on the graph was the individual learning style.

The academic performance assessments in this study included variety of levels according to Miller’s pyramid of assessment. For the level of “knows” and “knows how”, the academic performance was represented by the multiple choices question (MCQ) in-training examination. The test was composed of 100 MCQs included all Orthopedic subspecialties and basic science knowledge. The score was ranged from 0 to 100. For the level of “shows how”, the objective structural clinical examination (OSCE) score was reviewed. The test included 9 stations (1 station per 1 sub-specialty) and the score was ranged from 0 to 100 on each test. So, the total score of OSCE was 900. And, for the level of “does”, the global performance rating scale of the rotation along the whole academic year included 12 rotations (1 rotation per month) was examined. The score was ranged from 0 to 28. The scoring system was a 5-level Likert scale included 7 domains as moral-ethics, knowledge, psychomotor, intelligence, interpersonal, communication and responsibility skills. The MCQ in-training examination and OSCE were held at the 11-month of the academic year. All participants in every resident year did the same tests. While, the score of the global performance rating scale was reviewed at the first month of new academic year after all residents finished their all 12 rotations. The score reviews were performed altogether by two authors.

Statistical analysis

The statistical analysis was done using IBM SPSS Statistics for Windows 21.0 (IBM Corp, Armonk, NY). The categorical data was presented as number, percentage and ratio. The Shapiro-Wilk test was used to evaluate

the normality of the interval data. Mean and standard deviation (SD) was presented for normal distributed data. And, median and interquartile range (IQR) was presented for non-normal distributed data. The comparison of interval data was done using Analysis of the Variance (ANOVA) and Kruskal-Wallis H test depended on the data distribution. The statistically significant difference was considered as p < 0.05.

RESULTS

The response rate of the questionnaires was 100 %. The mean (SD) age of the participants was 30.4 (1.36) years old. There were 44 men (91.7 %) and 4 women (8.3 %). The mean (SD) GPA of medicine degree was

3.27 (0.33). The Kolb learning styles in Orthopedic residents included 18 assimilating (37.5 %), 12 converging

(25.0 %), 11 accommodating (22.9 %) and 7 diverging (14.6 %). There was no statistically significant difference of learning styles among each resident year, p = 0.810. (Table 1)

The comparative analysis of the academic performance scores demonstrated no statistically significant difference of MCQ in-training examination, OSCE and global performance rating scores among each Kolb learning style as p=0.789, 0.493 and 0.409, respectively. However, it was shown that assimilating and converging styles had the mean academic scores above the total average scores for all 3 assessments. While, the diverging styles had the mean score above the average score only in global performance rating score. The accommodating style had the mean score below the average score for all examinations (Table 2, 3 and 4).

TABLE 1. The distribution of Kolb learning styles in Orthopedic residents.

• chi-square demonstrated no statistically significant difference of learning style in each training year as p=0.810.

  
  

  
  

  TABLE 2. The relationship of Kolb learning styles and the multiple choices question (MCQ) in-training examination scores (n = 48).

  
  

  Kolb learning styles	MCQ in-training examination scores
  	Mean (SD)
  Diverging (7)	56.3 (5.38)
  Assimilating (18)	58.6 (9.38)
  Converging (12)	57.4 (12.3)
  Accommodating (11)	54.8 (9.54)
  Total (48)	57.1 (9.61)

  
  

• One way ANOVA demonstrated no statistically significant difference of scores among each learning style as p=0.789.

  
  

  
  

  TABLE 3. The relationship of Kolb learning styles and the objective structural clinical examination (OSCE) scores (n = 48).

  
  

  Kolb learning styles	OSCE scores
  	Mean (SD)
  Diverging (7)	604.4 (62.2)
  Assimilating (18)	639.6 (72.7)
  Converging (12)	650.6 (79.2)
  Accommodating (11)	612.8 (79.2)
  Total (48)	631.1 (76.7)

  
  

• One way ANOVA demonstrated no statistically significant difference of scores among each learning style as p=0.493.

  
  

  
  

  TABLE 4. The relationship of Kolb learning styles and the global performance rating scores (n = 48).

  
  

  
  

  Kolb learning styles	Global performance rating scores
  	Mean (SD)
  Diverging (7)	24.7 (0.84)
  Assimilating (18)	23.9 (1.81)
  Converging (12)	24.0 (1.39)
  Accommodating (11)	23.4 (2.05)
  Total (48)	23.8 (1.67)

  
  

• One way ANOVA demonstrated no statistically significant difference of scores among each learning style as p=0.407.

DISCUSSION

According to the result of this study, there was no statistically significant difference of academic performance scores regarding to Kolb learning styles. As a result, the hypothesis of this study was rejected. However, there was an interesting finding that the assimilating and converging style had the mean academic performance scores above the average scores for all assessments.

The assimilating and converging style shared the similar concept of experiential learning as the using of “abstract conceptualization” for the gathering experiences.1,2,7 The learning characteristics of these 2 learning styles could be defined as “deep learning strategy”.8,9 Deep learning strategy involved the effective learning processes as using intrinsic motivation, apparent understanding of the meaning of what was learnt, connecting the new to prior knowledge (constructivism) and critically evaluating of knowledge.8 And, this learning strategy had been reported to be associated with good academic achievement.8-10 Apart from “abstract conceptualization, these 2 learning styles also used “reflective observation” and “active experimentation” for the learning.

In the educational context application, the learning processes regarding to these 2 learning styles as reflective observation, abstract conceptualization and active experimentation should be promoted. The Kolb learning style in individual learner could be adapted regarding to the maturity and learning experience.11 Effective reflective observation and abstract conceptualization could be utilized by encouraging a “reflection” process for all available Orthopedic learning experiences. A reflection is “a complex and deliberate process of thinking about and interpreting experience in order to learn from it”. This learning tool could enhance deep integrated and lifelong learning to the learner.12,13 A reflection could be divided into 3 different levels of complexity as descriptive, practical and critical reflection. A critical reflection was emphasized as the most beneficial type.12,14 The important factors which could promote the effective reflection of the learners were suitable available time and environment.12-14 The instructor should plan the strategy which could provide available time for the Orthopedic residents to do reflection. This included the effective time management that was preserved for doing this learning process or using the assisting learning tools which allowed the learners to do the reflection at the suitable time such as e-learning or e-portfolio especially in the high service workload situation.14,15

Supporting the active experimentation in Orthopedic learning experience could be managed in various ways. The introduction of simulation for development of the

skill domain played an important role. The Orthopedic residents would be able to enhance their experiential learning gradually. The simulation allowed the residents to repeat their skill practice with safety environment.16,17 Julthongpipat et al. studied the development of simulation model for transradial catheterization practice in 18 fellows. The results demonstrated that the fellows satisfied with the simulation model and this training method provided the benefit as increasing familiarity and confidence to their practice.18 Many studies in the orthopedic field supported the benefit of using simulation in orthopedic learning experience. Angelo et al. reported the traditional learning combined with supportive simulation training and progressive assessment provided statistically significant better learning outcome compared with the traditional learning alone (p=0.011) for the arthroscopic shoulder joint surgery practicing in 44 orthopaedic residents.19 Yari SS et al reported the statistically significant improvement of performance score (p=0.003 and 0.035) using virtual simulator for the teaching of knee and shoulder arthroscopy in 18 Orthopaedic residents.16

Apart from the simulation, formative real-time and authentic assessment could also support active experimentation experiences in orthopedic residents. One effective assessment tool which could be done for this purpose was an “entrustable professional activities” (EPAs). EPAs had become one of favorable assessment tool in the Orthopedic field.20 Dwyer T et al. demonstrated that using EPAs combined with simulation training as a reliable assessment tool to assess the residents’ cognitive and psychomotor competencies for the management of patient undergoing surgery for ankle fracture, intertrochanteric fracture and total knee arthroplasty.21 The strength of EPAs was about the ability to do the assessment formatively which allowed the residents to gradually develop themselves along with the target each upgoing year.22,23

This study provided the new in-depth analysis in term of the relationship between Kolb learning styles and academic performance in every level of Miller’s pyramid of assessment. Even though, this research could not demonstrate the statistically significant positive- negative relationship between learning style and academic performance. However, the finding that the assimilating and converging learners had academic performance scores above the average scores in all domains could bring the attention to the instructors to facilitate Orthopedic learning experiences involving in effective reflective observation, abstract conceptualization and active experimentation. The limitations of this study included the sample size from the single training center which posed the problem of external validity and the small sample size which led to

statistical underpower in some aspects. We recommended research as a multi-center study involving more numbers of samples which might bring more significant finding in the future.

CONCLUSION

This study could not demonstrate the significant difference of academic performance among each Kolb learning style in Orthopedic residents. However, the assimilating and converging style had the consistent scores of all academic performance domains above the average scores. In term of application, the Orthopedic learning experience should emphasize on the development of reflective observation, abstract conceptualization and active experimentation to facilitate effective Orthopedic competency development and improving academic performance.

REFERENCES

1. Richard RD, Deegan BF, Klena JC. The Learning Styles of Orthopedic Residents, Faculty and Applicants at an Academic Program. J Surg Educ. 2014;71(1):110-8.

2. Harnroongroj T, Thanapipatsiri S, Nopparatjamjomras TN, Iramaneerat C. The Relationship Between Learning Styles, Academic Achievement, and Critical Thinking Skills Among Orthopedic Residents. Proceeding of Graduate Research Forum. 2022

3. Sand JN, Elison-Bowers P, Wing II TJ, Kendrick L. Experiential Learning and Clinical Education. Psychology. 2014;18(4):1-7.

4. Kolb DA. Experiential learning: Experience as the source of learning and development. Englewood Cliffs. New Jersey. Prentice-Hall; 1984.

5. McCarthy M. Experiential Learning Theory: From Theory to Practice. Journal of Business & Economics Research. 2016;14(3): 91-100.

6. Lerdlop W. Learning Styles of Students in the Faculty of Science and Technology. Suan Sunandha Rajabhat University, Bangkok. Bangkok: Suan Sunandha Rajabhat University; 2011.

7. Kolb AY, Kolb DA. The Kolb Learning Style Inventory Version

   3.1 2005 Technical Specifications. Experiential Based Learning Systems [Internet]. 2005 [Cited 2022 November 30]. Available from: http://www.learningfromexperience.com/.

8. Hayat AA, Shateri K, Amini M, Shokrpour N. Relationships between academic self-efficacy, learning-related emotions, and metacognitive learning strategies with academic performance in medical students: a structural equation model. BMC Med Educ. 2020;20:76.

9. Piumatti G, Guttormsen S, Zurbuchen B, Abbiati M, Gerbase

   MW, Baroffio A. Trajectories of learning approaches during a full medical curriculum: impact on clinical learning outcomes. BMC Med Educ. 2021;21:370.

10. Kusurka RA, Croiset G, Galindo-Garre F, Ten Cate O. Motivational profiles of medical students: Association with study effort, academic performance and exhaustion. BMC Med Educ. 2013; 13:87.

11. Quillin RC, Cortez AR, Pritts TA, Hanseman DJ, Edwards MJ, Davis BR. Surgical resident learning styles have changed with work hours. J Surg Res. 2016;200:39-45.

12. Mamede S, van Gog T, Moura AS, de Faria RM, Peixoto JM, Rikers RM, Schmidt HG. Reflection as a strategy to foster medical students' acquisition of diagnostic competence. Med Educ. 2012;46(5): 464-72.

13. Hatton N, Smith D. Reflection in teacher education: Towards definition and implementation. Teaching and Teacher Education. 1995;11(1):33-49.

14. Robertson K. Reflection in professional practice and education. Aust Fam Physician. 2005;34(9):781-3.

15. Branch WT, Paranjape A. Feedback and reflection: teaching methods for clinical settings. Acad Med. 2002;77:1185-8.

16. Yari SS, Jandhyala CK, Sharareh B, Athiviraham A, Shybut TB. Efficacy of a virtual arthroscopic simulator for Orthopaedic surgery residents by year in training. Orthop J Sports Med. 2018;6(11):2325967118810176.

17. Aim F, Lonjon G, Hannouche D, Nizard R. Effectiveness of virtual reality training in Orthopaedic surgery. Arthroscopy. 2016;32(1):224-32.

18. Julthongpipat K, Dumavibhat C, Towashiraporn K, Patpituck P. Development of Simulation Model for Transradial Catheterization Practice for Physicians. Siriraj Med J. 2022;74(9):570-4.

19. Angelo RL, Ryu RKN, Pedowitz RA, Beach W, Burns J, Dodds J, et al. A proficiency-based progression training curriculum coupled with a model simulator results in the acquisition of a superior arthroscopic Bankart skill set. Arthroscopy. 2015; 31(10):1854-71.

20. Wadey DM, Dev P, Buckley R, Walker D, Hedden D. Competencies for Canadian Orthopaedics surgery core curriculum. J Bone Joint Surg Br. 2009;91(12):1618-22.

21. Dwyer T, Wadey V, Archibald D, Kraemer W, Shantz JS, Townley J, et al. Cognitive and psychomotor entrustable professional activities: Can simulators help assess competency in trainees. Clin Orthop Relat Res. 2016;474:926-34.

22. Van Loon KA, Driessen EW, Teunissen PW, Scheele F. Experiences with EPAs, potential benefits and pitfalls. Medical Teacher. 2014;36(8):698-702.

23. Pinilla S, Lenouvel E, Cantisani A, Kloppel S, Strik W, Huwendiek S, et al. Working with entrustable professional activities in clinical education in undergraduate medical education: a scoping review. BMC Med Educ. 2021;21:172.

Routine Fogarty Catheter Occlusion of Fistula in Esophageal Atresia with Tracheoesophageal Fistula Surgery: A Retrospective Study

Darunee Sripadungkul, M.D.*,**, Noriko Miyazawa, M.D., Ph.D.*, Eri Shinto, M.D.***, Yuko Kanke, M.D.****, Haruto Fujita, M.D.*****

*Department of Anesthesiology, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan, **Department of Anesthesiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand., ***Department of Anesthesiology, Jikei University School of Medicine, Tokyo, Japan., ****Department of Anesthesiology, Tochigi Medical Center, Tochigi, Japan, *****Department of Anesthesiology, Keio University School of Medicine, Tokyo, Japan.

ABSTRACT

Objective: We aimed to analyze the outcomes of patients who underwent surgical repair of congenital esophageal atresia (EA) with a distal tracheoesophageal fistula (EA/TEF) or a Gross type C with successful routine Fogarty catheter occlusion of TEF.

Materials and Methods: We retrospectively reviewed the medical records of patients who underwent surgical repair of Gross type C with successful routine Fogarty catheter occlusion of fistula between April 2010 and November 2016. Results: Nineteen patients were enrolled and included for analysis. Mean gestational age was 38.7 (1.9) weeks with 2 (10.5%) neonates born prematurely. Mean birthweight was 2569.3 (425.3) g. Five (26.3%) patients required mechanical ventilation (MV) before surgical repair of TEF. Median post-operative required MV after TEF surgery was 4 (3-6) days. The most common of post-operative complications were wound dehiscence (10.5%) and pneumothorax (10.5%). Long-term complications were gastroesophageal reflux disease (36.8%) and tracheomalacia (31.6%).

Conclusion: The success rate of routine TEF occlusion with a Fogarty catheter was 86.4%. Routine Fogarty catheter occlusion of TEF can be used safely with experienced personnel, low incidence of aspiration and satisfied ventilation. There was no serious complication associated with placement of Fogarty catheter or catheter dislodgement, and it did not occur during any of the procedures.

Keywords: Congenital esophageal atresia (EA); Fogarty catheter; outcomes; tracheoesophageal fistula (TEF) (Siriraj Med J 2023; 75: 356-361)

INTRODUCTION

Congenital esophageal atresia (EA) is a rare congenital anomaly by complete interruption of the esophagus with a prevalence of 1.7 per 10,000 live births.1 Congenital EA with a distal tracheoesophageal fistula (EA/TEF), or Gross type C, is the most common type, comprising 85% of EA cases.2 This congenital anomaly is often associated with the anomalies described by the acronym VACTERL

(vertebral anomalies, imperforated anus, congenital heart disease (CHD), tracheoesophageal anomalies, renal anomalies and limb anomalies). Surgical repair and anesthetic management are challenging because of the difficulty in management of airway and ventilation, control of adverse hemodynamic from associated anomalies of cardiovascular system and the thoracotomy procedure.2-4

Corresponding author: Darunee Sripadungkul Email: daruneesripa@gmail.com

Received 5 January 2023 Revised 19 March 2023 Accepted 19 March 2023 ORCID ID:http://orcid.org/0000-0003-2228-2224 https://doi.org/10.33192/smj.v75i5.260704

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

The ideal management of most patients with EA/ TEF might be the ligation of the fistula and primary esophageal repair performed in a single operation. Nevertheless, patients with persistent aspiration and recurrent pneumonia from the existing fistula induce poor medical conditions, disabling the neonates to withstand corrective surgery performed under general anesthesia. Use of a Fogarty catheter to occlude the fistula, by using rigid or flexible bronchoscopy, can be used to improved lung function and their medical condition.2,5

The classic technique for airway and ventilation management for TEF repair is to maintain spontaneous ventilation and pass the endotracheal tube (ET) tip distal to fistula.6 Despite this technique, ineffective ventilation may occur because of inadvertent placement of the ET in the fistula, unintentional ventilation of the fistula, or massive gastric distention.7 When TEF is very near or at the carina, this technique becomes impossible and unreliable.8 Alternative technique is to controlled ventilation with muscle relaxant and placement a Fogarty catheter in the fistula under rigid or flexible bronchoscopy for separation of the airway and gastrointestinal (GI) tract. Previous studies have described the use of Fogarty balloon occlusion in unstable patients or in H-type fistulas that may be difficult to identify, and re-operative procedures.5,9,10 The benefits of routine use of Fogarty catheters in the repair of TEF were reduction of aspiration, improved ventilation, safely and expeditiously.11

We aimed to analyze the outcomes of patients who underwent surgical repair of Gross type C EA/TEF with successful routine Fogarty catheter occlusion of tracheoesophageal fistula in a single institution.

MATERIALS AND METHODS

Study design

After approval of the institutional review board (H28b- 135), we retrospectively reviewed the medical records of patients who underwent surgical repair of Gross type C EA/TEF between April 2010 and November 2016 at Tokyo Metropolitan Children’s Medical Center. Inclusion criteria included patients who underwent surgical repair of Gross type C EA/TEF with successful routine Fogarty catheter occlusion of fistula. We exclude the patient who underwent surgical repair of Gross type C EA/TEF with unsuccessful routine Fogarty catheter occlusion of fistula. The data collected and analyzed consist of three sections. The first section evaluated patient characteristics, including gender, gestational age (GA), birth weight (BW), Apgar score, day of life (DOL) at surgery, body weight at surgery, and associated anomalies. The second section evaluated surgical management, including initial surgery

and other surgical procedures performed on the same admission, and the distance between the upper and lower esophageal ends (esophageal gab). The third section evaluated anesthetic management, including pre-operative events (i.e., desaturation (SpO2 < 90%)12, tracheal intubation or tracheostomy pre-operatively, inotropic support), intra- operative events (i.e., desaturation, difficult ventilation, and inotropic support), intra-operative outcomes (surgical time, anesthetic time, fluid management, urine output and blood loss) and post-operative outcomes (duration of received mechanical ventilation (MV), prolonged post-operative MV after TEF repair (≥ 7 days)13, post- operative complications and long-term complications).

All Gross type C EA/TEF repairs were performed in the lateral decubitus position via thoracotomy. No endoscopic repairs were performed in any of the cases. All patients from the neonatal intensive care unit (NICU) had an intravenous line before surgery. The patients were gently ventilated with a bag and mask before tracheal intubation. We examined all patients with flexible bronchoscopy (Olympus BF-N20 Fiber Bronchoscope, outer diameter 2.2 mm) through the ETT lumen to assess the location and size of the TEF, after which we extubated and inserted a Fogarty catheter (Fogarty arterial embolectomy catheter, 3 Fr, balloon diameter 5 mm, Edwards Lifesciences, Irvine CA, USA). During laryngoscopy, a Fogarty catheter was inserted until the tip reached the mid-trachea, followed by reintubation with an uncuffed endotracheal tube. The tip of the Fogarty catheter was pre-bent to face backward during insertion. Immediate, flexible bronchoscopy was performed again to guide a Fogarty catheter into the TEF until the balloon disappeared and inflated with 1 mL of air. We performed TEF occlusion with a Fogarty catheter in all patients. In addition to standard American Society of Anesthesiologists (ASA) monitoring, patients had invasive pressure monitoring or had percutaneous inserted central catheter (PICC) line was placed pre- operatively during the EA/TEF repair. During anesthetic maintenance, general anesthesia was maintained by remifentanil 0.1-0.3 μg/kg/min, fentanyl 1 μg/kg/dose,

midazolam 0.1 mg/kg/dose, rocuronium 0.2-0.3 mg/kg/ dose, and a low end-expired concentration of sevoflurane. After the surgery, all patients retained an endotracheal tube or tracheostomy and were on MV during their transfer to the NICU. Post-operative analgesia was provided primarily with an opioid (fentanyl or morphine hydrochloride), dexmedetomidine, and acetaminophen. Post-operative sedation was provided with midazolam.

Statistical analysis

Data analysis was performed using STATA 10.1. We

used descriptive statistics to describe patient characteristics, surgical management and anesthetic management (intra- operative and post-operative outcomes). Categorical data was presented as number and percentage. Continuous data was analyzed using the Shapiro-Wilk test for normality test and presented as mean (standard deviation) and median (interquartile range).

We calculated the proportion using the number of participants with non-missing data. The estimated required sample size was 18 patients as calculated using the formula for an infinite population proportion with a proportion (p) of 0.754 and calculated error (d) of 0.20. The total population consisted of 19 patients. The study was analyzed and presented with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.

RESULTS

A total of 22 patients were identified as having undergone surgical repair of Gross type C EA/TEF. We excluded 3 patients who underwent unsuccessful routine Fogarty catheter occlusion of fistula. Nineteen patients were enrolled and included for analysis.

Three patients (13.6%) who failed routine Fogarty catheter occlusion of fistula; however, the medical records were not recorded cause of failure to perform this procedure. Two patients had multiple severe associated anomalies (i.e., preterm, low birth weight (LBW), congenital tracheal stenosis (CTS), CHD score ≥ 3 on the Risk Adjustment for Congenital Heart Surgery 1 (RACHS-1),14,15 pre-operatively desaturation, cardiac arrest which had cardiopulmonary resuscitation (CPR) and on inotropic support, and had distance between the upper and lower esophagus ends

≥ 10 mm. Meanwhile, one patient had CHD (RACHS-1 score < 3), and vocal cord paralysis.

Patient characteristics

Twelve (63.2%) patients were male. Mean GA was

38.7 (1.9) weeks with 2 (10.5%) neonates born prematurely.

Mean BW was 2569.3 (425.3) g with 9 (47.4%) neonates having a LBW (BW less than 2500 g). Median Apgar score at 1 and 5 minutes were 8 (8-9) and 9 (8-9). The patients with type C EA/TEF underwent surgery repair on median day of life (DOL) 1 (1-1) and mean body weight at surgery was 2453.1 (375.3) g. Total associated anomalies were found in 11 (57.9%) patients. Congenital heart diseases (CHD) were the most frequently occurring comorbidities (n=11 patients; 57.9%). Nine patients with CHD scored < 3 on RACHS-1 and two patients had a RACHS-1 score ≥ 3. The associated anomalies with VACTREL were found in 4 (21.1%) patients. The

associated anomalies with others (i.e., CTS, cleft lip and cleft palate, aspiration pneumonitis, and chromosomal abnormalities (Trisomy 21)) were found in 3 (15.8%) patients.

Surgical management

In the primary TEF repairs were found in 18 patients, 16 patients underwent TEF repair, and 1 underwent TEF repair with colostomy due to associated imperforate anus. Meanwhile, 1 patient underwent TEF repair with gastrostomy and colostomy due to associated cloacal malformation. The other surgical procedures performed on the same admission included early revision of their TEF repair (staged TEF repair) in 1 (5.3%) patient, gastrostomy and colostomy due to imperforate anus in 1, while 3 required cardiac surgery before their initial discharge home. In addition, the distance between the upper and lower esophagus ends had a distance ≥ 10 mm were found in 5 (26.3%) patients.

Anesthetic management

In pre-operative events, four patients (21.1%) had desaturation, four patients (21.1%) required intubation due to aspiration pneumonia, CHD, LBW, or prematurity, one patient (5.3%) had tracheostomy due to CTS, and two patients (10.5%) required inotropic support before surgery. Intra-operatively, twelve patients (63.2%) had desaturation, three patients (15.8%) difficult ventilation, and five patients (26.3%) required inotropic support during operation.

We routinely performed Fogarty catheter occlusion of tracheoesophageal fistula in all patients with successfully in 19 of 22 patients (86.4%). Table 1 shows anesthetic management (intra-operative and post-operative outcomes) to evaluate surgical time, anesthetic time, fluid management, urine output, blood loss, duration of received MV, prolonged post-operative MV, post-operative complications, and long-term complications. Five (26.3%) patients required MV before surgical repair of TEF. Median pre-operative required MV in five patients was 1 (0-2) day. Median post-operative required MV after TEF surgery was 4 (3-6) days. Three patients (15.8%) required prolonged post- operative MV that had pre-operative MV. All patients had invasive pressure monitoring during the EA/TEF repair. A percutaneous inserted central catheter (PICC) line was placed pre-operatively in four (21.1%) patients.

DISCUSSION

We included 19 patients in the study who underwent surgical repair of Gross type C EA/TEF with successful routine Fogarty catheter occlusion of fistula. All patients

TABLE 1. Anesthetic management (intra-operative and post-operative outcomes) (n=19)

Gastroesophageal reflux disease (GERD)

Tracheomalacia

7 (36.8%)

6 (31.6%)

Abbreviations: SD, standard deviation; IQR, interquartile range; n, number; %, percentages

were operated on by the same pediatric surgical team with virtually the same anesthesia methods. Anesthetic management of Gross type C EA/TEF generally depends on patient comorbidity, location and size of TEF, anesthetist preference, and local hospital practice. Three patients (15.8%) required prolonged post-operative MV (≥ 7 days). The most common post-operative complications after TEF surgery were wound dehiscence (10.5%), and pneumothorax (10.5%). Long-term complications after TEF surgery were GERD (36.8%) and tracheomalacia (31.6%).

Pre-operative mechanical ventilation occurred in five of 19 patients (26.3%) in this study, similar to a report from previous study where 15 of 53 patients (28.3%) were intubated and mechanically ventilated before surgery.16 By comparison, another study showed that 20 of 106 patients (18.9%) were intubated before the theater.4

Congenital heart disease was the most frequent comorbidity in our study, occurring in 11 patients (57.9%),

similar to the report from previous study wherein eight of 15 patients had CHD (53.3%).3 However, congenital heart disease may underestimate during the pre-operative period because of pre-operative transthoracic echocardiography in children reported the concordance was 77.7%. Therefore, we should concern of unexpected cardiac events during the peri-operative period.17 In this study, there were two preterm patients (10.5%) and LBW in 9 patients (47.4%). The previous study also reported that there were preterm patients in three (20%), LBW in five (33.3%), and very low birth weight (VLBW) in one (6.7%) of 15 patients.3 Previous study reported their practice included routine bronchoscopy, muscle paralysis, ventilation before intubation, and all large TEFs occluded with a Fogarty catheter same as at our hospital.18 The advantages of flexible bronchoscopy include assessment of the exact location and size of the TEF, placement of a catheter to aid in surgical identification of the TEF, and assessment of tracheomalacia or vascular rings.6 Complications of flexible bronchoscopy in very small patients have been

well described, including oxygen desaturation, coughing, epistaxis, laryngospasm, bronchospasm, and life-threatening complications (i.e., tension pneumothorax).19

Previous studies have described the use of Fogarty balloon occlusion in unstable patients or in H-type fistulas, and re-operative procedures.5,9,10 The benefits of routine use of Fogarty catheters in the repair of TEF were reduction of aspiration, improved ventilation, safely and expeditiously.8,11,20 After the TEF was blocked with the balloon of the catheter, the patient could be mechanically ventilated with positive pressure even if the surgical procedure was prolonged. In our study, the success rate of routine TEF occlusion with a Fogarty catheter was 86.4% (19 of 22 patients) which our patients had more than the previous study that had only 5 patients (100%) of successful routine TEF occlusion with a Fogarty catheter.11 There was no serious complication associated with placement of Fogarty catheter or catheter dislodgement, and it did not occur during any of the procedures.

In our study, three patient (15.8%) required post- operative prolonged MV. One patient did not have CHD, but was preterm, LBW, and required inotropic support. One patient was associated with CHD (RACHS-1 score

< 3), LBW, CTS, required tracheostomy pre-operatively, and required staged operation. In addition, the remaining one patient was associated with CHD (RACHS-1 score

≥ 3), and required intubation pre-operatively. Previous studies suggested that peri-operative risk factors for prolonged MV following cardiac surgery in pediatric patients were pre-operative MV, younger age, LBW, RACHS-1 score ≥ 3, acute kidney injury, respiratory infection, a higher dose of inotropes, and pulmonary hypertension.13,21

The most common post-operative complications in this study were wound dehiscence in 2 (10.5%) and pneumothorax in 2 (10.5%) patients, while other complications were anastomotic leakage in 1 (5.3%) and anastomotic stricture in 1 (5.3%) patient. Different from the previous study that found anastomotic stricture in 43-71.9%, anastomotic leakage in 11.5-18%, and recurrent distal TEF (type C) in 5-9%.22,23 Meanwhile, long-term complications in this study were found gastroesophageal reflux disease (GERD) in 7 (36.8%) and tracheomalacia in 6 (31.6%) patients, while in the previous study were found GERD in 73 (79.3%) and tracheomalacia in 29

(31.5%) patients.22

The results contribute a clearer understanding of routine Fogarty catheter occlusion of fistula in patients who underwent surgical repair of Gross type C EA/TEF that it may be suitable for patients who had the mean BW was 2569.3 (425.3) g. There was no serious complication

associated with placement of Fogarty catheter or catheter dislodgement, and it did not occur during any of the procedures.

The study has limitations: (a) it was based on a single center, local practice pattern, (b) it had a retrospective design, which could have a selection bias, missing clinical data and limit the cause of failed routine TEF occlusion with a Fogarty catheter, and (c) although our study sample size more than previous studies, but it might constrain its generalizability. However, we need larger sample size to make a firm conclusion. Further study is recommended to assess prospective data from large numbers of patients among a cross-section of institutions.

CONCLUSION

The success rate of routine TEF occlusion with a Fogarty catheter was 86.4%. Routine Fogarty catheter occlusion of TEF can be used safely with experienced personnel, low incidence of aspiration and satisfied ventilation. With the increase in the number of cases, there was no serious complication associated with placement of Fogarty catheter or catheter dislodgement, and it did not occur during any of the procedures.

ACKNOWLEDGMENTS

We thank (a) the anesthesiologists at Tokyo Metropolitan Children’s Medical Center for their help and assistance (b) Miss Piyanan Suparattanagool, Clinical Epidemiology Unit, for assistance with the biostatistics and (c) Professor Polpun Boonmak, Faculty of Medicine, Khon Kaen University, Thailand, for his valuable suggestion and encouragement.

Conflict of Interest Statement

All authors have no conflict of interest.

REFERENCES

1. Khan S, Matta SR. Congenital anomalies: Esophageal atresia and tracheoesophageal fistula. In: Kliegman RM, Geme JS, Blum NJ, Shah SS, Tasker RC, Wilson KM, eds. Nelson textbook of pediatrics. 21th ed. Philadelphia, PA: Elsevier; 2019. p.1929- 31.

2. Uzumcugil F. Anesthetic management of tracheo-esophageal fistula. Curr Chall Thorac Surg. 2022;4:27. doi:10.21037/ccts- 20-183

3. Yang CF, Soong WJ, Jeng MJ, Chen SJ, Lee YS, Tsao PC, et al. Esophageal atresia with tracheoesophageal fistula: ten years of experience in an institute. J Chin Med Assoc. 2006;69(7):317-

   21. doi:10.1016/S1726-4901(09)70265-5

4. Knottenbelt G, Costi D, Stephens P, Beringer R, Davidson A. An audit of anesthetic management and complications of tracheo-esophageal fistula and esophageal atresia repair. Paediatr Anaesth. 2012;22(3):268-74. doi:10.1111/j.1460-9592.2011.03738.x

   
   

5. Chang JW, Choo O, Shin YS, Hong J, Kim C. Temporary closure of congenital tracheoesophageal fistula with Fogarty catheter. Laryngoscope. 2013;123(12):3219-22. doi:10.1002/ lary.24164

6. Ho AM, Dion JM, Wong JC. Airway and Ventilatory Management Options in Congenital Tracheoesophageal Fistula Repair. J Cardiothorac Vasc Anesth. 2016;30(2):515-20. doi:10.1053/j. jvca.2015.04.005

7. Alabbad SI, Shaw K, Puligandla PS, Carranza R, Bernard C, Laberge JM. The pitfalls of endotracheal intubation beyond the fistula in babies with type C esophageal atresia. Semin Pediatr Surg. 2009;18(2):116-8. doi:10.1053/j.sempedsurg.2009.02.011

8. Ho AM, Wong JC, Chui PT, Karmakar MK. Case report: Use of two balloon-tipped catheters during thoracoscopic repair of a type C tracheoesophageal fistula in a neonate. Can J Anaesth. 2007;54(3):223-6. doi:10.1007/BF03022644

9. Ratan SK, Rattan KN, Ratan J, Bhatia V, Sodhi PK, Bhatia M. Temporary transgastric fistula occlusion as salvage procedure in neonates with esophageal atresia with wide distal fistula and moderate to severe pneumonia. Pediatr Surg Int. 2005;21(7):527-

   31. doi:10.1007/s00383-005-1407-8

10. Richenbacher WE, Ballantine TV. Esophageal atresia, distal tracheoesophageal fistula, and an air shunt that compromised mechanical ventilation. J Pediatr Surg. 1990;25(12):1216-8. doi:10.1016/0022-3468(90)90507-6

11. Pepper VK, Boomer LA, Thung AK, Grischkan JM, Diefenbach KA. Routine Bronchoscopy and Fogarty Catheter Occlusion of Tracheoesophageal Fistulas. J Laparoendosc Adv Surg Tech

    A. 2017;27(1):97-100. doi:10.1089/lap.2015.0607

12. Stollar F, Glangetas A, Luterbacher F, Gervaix A, Barazzone- Argiroffo C, Galetto-Lacour A. Frequency, Timing, Risk Factors, and Outcomes of Desaturation in Infants With Acute Bronchiolitis and Initially Normal Oxygen Saturation. JAMA Netw Open. 2020;3(12):e2030905. doi:10.1001/jamanetworkopen.2020.30905

13. Polito A, Patorno E, Costello JM, Salvin JW, Emani SM, Rajagopal S, et al. Perioperative factors associated with prolonged mechanical ventilation after complex congenital heart surgery. Pediatr Crit Care Med. 2011;12(3):e122-6. doi:10.1097/PCC.0b013e3181e912bd

14. Jenkins KJ, Gauvreau K, Newburger JW, Spray TL, Moller JH, Iezzoni LI. Consensus-based method for risk adjustment for surgery for congenital heart disease. J Thorac Cardiovasc Surg. 2002;123(1):110-8. doi:10.1067/mtc.2002.119064

15. Jenkins KJ, Gauvreau K. Center-specific differences in mortality: Preliminary analyses using the Risk Adjustment in Congenital Heart Surgery (RACHS-1) method. J Thorac Cardiovasc Surg. 2002;124(1):97-104. doi:10.1067/mtc.2002.122311

16. Diaz LK, Akpek EA, Dinavahi R, Andropoulos DB. Tracheoesophageal fistula and associated congenital heart disease: implications for anesthetic management and survival. Paediatr Anaesth. 2005;15(10):862-9. doi:10.1111/j.1460-9592. 2005.01582.x

17. Sanphasitvong V, Jim LY, Tantiwongkosri K. Impact of Accuracy of Preoperative Transthoracic Echocardiography on Complex Congenital Heart Surgery in Pediatrics. Siriraj Med J. 2019;71(6): 480-5. https://doi.org/10.33192/Smj.2019.71

18. Andropoulos DB, Rowe RW, Betts JM. Anaesthetic and surgical airway management during tracheo-oesophageal fistula repair. Paediatr Anaesth. 1998;8(4):313-9. doi:10.1046/j.1460-9592. 1998.00734.x

19. Atzori P, Iacobelli BD, Bottero S, Spirydakis J, Laviani R, Trucchi A, et al. Preoperative tracheobronchoscopy in newborns with esophageal atresia: does it matter? J Pediatr Surg. 2006; 41(6):1054-57. doi:10.1016/j.jpedsurg.2006.01.074

20. Reeves ST, Burt N, Smith CD. Is it time to reevaluate the airway management of tracheoesophageal fistula? Anesth Analg. 1995;81(4):866-9. doi:10.1097/00000539-199510000-

    00036

21. Tabib A, Abrishami SE, Mahdavi M, Mortezaeian H, Totonchi Z. Predictors of Prolonged Mechanical Ventilation in Pediatric Patients After Cardiac Surgery for Congenital Heart Disease. Res Cardiovasc Med. 2016;5(3):e30391. doi:10.5812/cardiovascmed. 30391

22. Friedmacher F, Kroneis B, Huber-Zeyringer A, Schober P, Till H, Sauer H, et al. Postoperative Complications and Functional Outcomeafter Esophageal Atresia Repair: Results from Longitudinal Single-Center Follow-Up. J Gastrointest Surg. 2017;21(6):927-

    35. doi:10.1007/s11605-017-3423-0

23. Lal DR, Gadepalli SK, Downard CD, Ostlie DJ, Minneci PC, Swedler RM, et al. Challenging surgical dogma in the management of proximal esophageal atresia with distal tracheoesophageal fistula: Outcomes from the Midwest Pediatric Surgery Consortium. J Pediatr Surg. 2018;53(7):1267-72. doi:10.1016/j.jpedsurg. 2017.05.024

The Feasibility and Outcomes of Retrograde Intrarenal Surgery to Treat Staghorn Renal Calculi

Sunai Leewansangtong, M.D., Karn Liangkobkit, M.D., Chaiyong Nualyong, M.D., Sittiporn Srinualnad, M.D., Bansithi Chaiyaprasithi, M.D., Tawatchai Taweemonkongsap, M.D., Kittipong Phinthusophon, M.D., Siros Jitpraphai, M.D., Patkawat Ramart, M.D., Varat Woranisarakul, M.D., Chalairat Suk-ouichai, M.D., Thawatchai Mankongsrisuk, M.D., Thitipat Hansomwong, M.D., Kantima Jongjitaree, M.D., Ekkarin Chotikawanich, M.D.

Division of Urology, Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

ABSTRACT

Objective: To study the safety and efficacy of retrograde intrarenal surgery (RIRS) in patients with staghorn stones. Materials and Methods: This retrospective observational study was carried out between May 2016 and October 2020, which is when we performed RIRS in staghorn stone patients. Medical records of all patients with this condition in the database of Siriraj Hospital were reviewed. A total of 35 patients were eligible for this study. Descriptive statistics were used to assess the safety and efficacy of RIRS in patients with staghorn stones.

Results: In total, 31.43% of patients were stone-free after the first round of RIRS and 59.55% achieved stone-free status after the second procedure. The stone-free rate did not increase after a second round of RIRS. The median size of all staghorn stones was 3.1 cm. Unfortunately, we found two sepsis patients in this study. We also found eight events of minor complications, including fever and minimal ureteric injury in 54 sessions of RIRS we performed. However, no major injuries or bleeding requiring blood transfusion was identified.

Conclusion: Percutaneous nephrolithotomy (PCNL) is still considered the first-line therapy for kidney stones over two centimeters with a favorable stone-free rate. But, in some patients with limitations such as uncorrectable coagulopathies, impaired renal function, single kidney, and morbid obesity, RIRS is a good choice to reduce the likelihood of serious complications and have an acceptable stone-free rate. However, a prospective study should be performed to confirm these findings.

Keywords: Retrograde intrarenal surgery; staghorn stones; percutaneous nephrolithotomy; complication; stone-free rate (Siriraj Med J 2023; 75: 362-368)

INTRODUCTION

Urolithiasis is a major public health problem in Northeastern and Northern Thailand. It can cause flank pain, nausea, pain when urinating, bloody urine, and urinary tract infection. In a study from 2020, urolithiasis was found mostly in middle-aged and the elderly between 50-69.1 The highest incidence of urolithiasis in Thailand is in the Northeast of the country, accounting for 16.9% of all cases.2

Although there is no clear definition, staghorn stones commonly refer to stones with more than one branching of the collecting system that may divide completely or partially depending on the level of occupancy.3,4 Staghorn stones are often associated with infection or metabolic abnormalities, and can lead to obstruction, kidney loss, sepsis, and death if left untreated.5,6

According to AUA and EAU guidelines, since percutaneous nephrolithotomy (PCNL) provides a higher

Corresponding author: Ekkarin Chotikawanich E-mail: ekkarinc@yahoo.com

Received 27 February 2023 Revised 14 March 2023 Accepted 23 March 2023 ORCID ID:http://orcid.org/0000-0003-3914-2770 https://doi.org/10.33192/smj.v75i5.261510

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

stone-free rate than Shockwave Lithotripsy (SWL) or Ureteroscopy (URS), PCNL is considered as first-line therapy for symptomatic patients who have a stone burden >20 mm.7,8

Open surgery or laparoscopic/robotic-assisted procedures are alternative modalities with a good stone- free rate.3 However, some patients are not suited for this treatment or may prefer less invasive procedures. Hence, we attempted to find other modalities that could provide a stone-free rate (SFR) similar to PCNL, with a lower incidence of complications and reduced hospitalizations. We found many studies with retrograde intrarenal surgery (RIRS) in larger stones (>20 mm), with higher stone-free rates and fewer complications than PCNL due to well-developed instruments, such as the flexibility or size of the endoscope, accessory equipment, and techniques.9 Therefore, we aimed to study the safety and efficacy of the retrograde endoscopic technique in

patients with staghorn stones treated at our hospital.

MATERIALS AND METHODS

This was a retrospective observational study. At our institute, we performed retrograde intrarenal surgery in staghorn stone patients in May 2016. After the study was approved by the Ethics Committee (COA no. Si 153/2022), medical records of all patients with staghorn stones treated by RIRS in the database of our tertiary referral university hospital from May 2016 to October 2020 was reviewed. We excluded a complete staghorn stone, patients under 18 or those who had received other modalities in their first attempt such as PCNL, SWL, and open surgery, and those who denied treatment, had incomplete data, and patients who failed to follow-up. In total, we had 35 patients who underwent RIRS as their first lithotripsy attempt and were eligible for this study. Patients who possessed staghorn stones in both kidneys were considered as two subjects with a stone in each kidney. However, patients who had a non-staghorn stone on the contralateral side were counted as one subject.

The size of the stones, maximum, and mean of the Hounsfield Units (HU) were measured using the same “DICOM viewer” program and the same observer in all patients. In X-ray results, we used the widest diameter. In computerized tomography (CT) results, we used the largest diameter from both coronal and axial views.

The operative notes and techniques were reviewed, including ureteral access sheath size and fluoroscopy time. Estimated blood loss and operative time was collected by reviewing the anesthesiologist’s record, and the complications, both immediate and delayed were recorded by reviewing IPD charts, operative notes, and

OPD records up to a maximum of 6 months after the latest procedure. The glomerular filtration rate (GFR) was obtained in the same visit or at least two weeks before every operation.

Currently, intraoperative and postoperative complications are commonly classified according to modified Satava and modified Clavien classification systems.10-16 In our research, post-operative problems were categorized into four groups: fever, sepsis, others, and no complications summarized by the modified Clavien classification system. We defined sepsis according to the positive hemoculture result. To classify peri- operative complications, we employed the modified Satava classification system. However, we still specified specific complications along with classification grading to obtain a clear perspective.

There were three urologists involved in our project. After general anesthesia, cystoscopy, sheath 22Fr, and 30-degree lens were used in all cases. Hydrophilic tip wire was passed inside to the renal pelvis under a fluorograph. A double-lumen catheter was replaced over the guidewire, and the super-stiff guidewire was inserted into the hole of the catheter. Ureteral access sheath, 11/13Fr or 12/14Fr, replaced the catheter over the stiff wire. Afterwards, a flexible video ureteroscope URF-V – Olympus was inserted. Renal stones were identified and disintegrated with Ho-YAG laser setting 1J 20Hz. A retrograde pyelogram was performed, and a DJ stent inserted.

After the operation, stone analysis was carried out using the Fourier transform infrared spectroscopy (FTIR) technique at our institute after authorization by nephrologists. The maximum compound from stone analysis was used to represent the etiology of the stone of the patient.

Stone-free was defined as no residual stone or a stone fragment less than 2 mm on a standard radiograph, CT scan, or sonography (depending on the type of stone) at a maximum of six-month follow-up after the latest procedure. The remaining stones were categorized into a lower pole and a non-lower pole.

The data was divided into four parts as follows: patient data including gender, age, race, underlying disease, medication, glomerular filtration rate, hydronephrosis, and previous treatment history. Surgical data included operative time, blood loss during surgery, size of access sheath used, perioperative complications, and fluoroscopy time. Post-surgery data included number of procedures performed, post-operative complications, glomerular filtration rate, and post-treatment stone-free rate. Last but not least, stone data included size, type, location,

opacity, Hounsfield Units, and stone analysis.

Descriptive statistics were used to characterize populations. Qualitative variables such as gender was presented as frequency and percentage. Quantitative variables such as age, size, and Hounsfield Units, which are non-normal distributions of continuous data, were represented by the median and min-max or IQR values. The frequency of stone-free rates and complications were reported as number and percentage. Unfortunately, the number of patients was limited, so we were unable to analyze the statistic module.

RESULTS

A total of 36 participants in the study were divided into 12 men, and 23 women, with a median age of 63 (IQR 56-73). The underlying medical conditions were as follows: hypertension, 25 people (71.43%), hyperlipidemia,

19 people (54.29%), diabetes, 15 people (42.86%), chronic kidney disease, nine people (25.71%), any type of cancer, two people (5.71%), and no underlying disease, four people (11.43%), respectively.

The median size of all staghorn stones was 3.1 cm, with a range from 1.5-7.16 cm, and 10 people had it on the right and 25 on the left side. The median of maximum Hounsfield Units was 1226 HU (IQR 813- 1661) and the median of the mean of Hounsfield Units

was 950 HU (IQR 584-1332). Twelve subjects (34.29%) had radiopaque stones and 21 (60%) had radiolucent stones, and the remainder were unspecified (5.71%). In total, 13 people had hydronephrosis (37.14%). The demographic data is shown in Table 1.

In this study, we divided stones into three main types: calcium, non-calcium stones, and uric stones. The most common type were calcium-based stones, accounting for 18 (51.4%), followed by nine uric stones (25.7%), five non-calcium stones (14.3%), and three uncategorized stones (8.6%).

The peri-operative and post-operative outcomes are shown in Table 2. The stone-free rate was 31.43%, and 59.55% after the first and second procedures, respectively. The stone-free rate did not increase after the second procedure.

For the operation, we used ureteral access sheaths size 11/13Fr or 12/14Fr in almost all cases. The median operative time was 80 minutes for the first procedure, 60 minutes for the second, 35 minutes for the third, and 90 minutes for the fourth procedure, with an estimated blood loss of less than 30 ml in each session, except for patients who switched to PCNL.

A total of 10 patients were pre-stented for RIRS due to a narrowed or swollen ureter, and inability to access the stones. Nine underwent pre-stenting before the first

TABLE 1. Demographic data.

TABLE 2. Perioperative outcomes.

RIRS session and one patient before the second RIRS session. Intra-operative problems of this step were seen in two subjects with a ureteral injury, which falls under Grade 1 of the modified Satava classification system. Meanwhile, the patient had a low-grade fever during post-operative problems. All cases resolved after stenting and routine post operative care.

We had a total of 35 patients who underwent RIRS as the first step. Grade 1 and 3A complications of the modified Clavien classification were noted in four and two patients respectively. Two patients had a fever, two were septic, one had acute urinary retention, and one had both ureteral injury and fever. The remaining 28 patients had no complications. One patient also had pure ureteral injury, not including the other patient mentioned before, accounting for Grade 1 of the modified Satava classification system. All patients recovered after conservative treatment. The stone-free success rate of the first procedure was 31.43% (11 patients). The remaining stones were found in the lower pole accounting for 95.83% (23 patients) and in the non-lower pole location for 29.17% (7 patients). In some cases, there was more than one location of the remaining stone.

During the second procedure, six patients stopped operative management, with three switching to medical treatment, and two failing to follow-up. The remaining stones were all lower pole stones characterized by four

calcium base stones, one uric, and one unknown type. The size was about 0.8-2.5 cm. The remaining 18 patients in this group were divided into two subgroups, including three patients who underwent PCNL and 15 who underwent RIRS. In the RIRS group, we found three patients that had a fever (Grade 1 of modified Clavien), however, the other 12 had no complications. The stone-free rate was 60.00% (9 out of 15 patients) for this procedure and the cumulative stone-free rate for the RIRS group was 59.55%. Since some patients had more than one site of remaining stones, they were in both the lower pole and non-lower pole group for three patients (50%) and three patients (50%) in the lower pole group. In terms of complications, we found two patients with fever, while the other patient had a serious bleeding complication and required transfusion, which falls under Grade 1 and 2 of the modified Clavien classification. Also, PCNL did not improve the stone-free rate in the second procedure. Remaining stones from PCNL were found in the lower pole of all three patients, accounting for 100%.

In the third and fourth procedures, we had only five patients in both groups, and we didn’t notice any complications and the stone-free rate did not increase significantly. We found only one patient who was stone- free from PCNL in the third procedure. It was difficult to use statistical methods and percentage reports in these groups because the population was too small.

In summary, a total of four patients underwent PCNL due to stone burden. The number of patients in this group was too small to conclude and justify the stone-free rate and surgical complications for PCNL. However, in these cases, three patients had an estimated blood loss of 250, 300, and 600 ml, respectively, but only one person required a transfusion. The estimated blood loss in the PCNL group tended to be higher than RIRS. The operative time was more than 120 minutes in most cases, which is higher than the average of RIRS as mentioned above.

DISCUSSION

Percutaneous kidney stone surgery is considered by both the American Urological Association (AUA) and European Association of Urology (EAU) as first- line therapy for kidney stones over two centimeters in size and branching calculi, with a single-stage rate of 83%-95% stone-free.7,8 The indication for PCNL includes many factors such as stone size, stone location, patient, and stone composition, all of which affect the surgeon’s decision. Stones larger than 2 cm, staghorn stones, and lower pole stones more than 1 cm are not suitable for SWL. Meanwhile, obese patients or patients with distal obstruction preventing the passage of stone fragments are suitable for PCNL. The stone composition and hardness are also factors to be concerned about. For example, the PCNL method is preferred to treat cystine stones.3,7,8

Although we already have past data on stone-free rates, data on complications was lacking. In the past, there was no definitive criteria for PCNL complications. The decision was made by the surgeon who reported on complications, and mostly focused on intraoperative periods making it difficult to compare the actual complications of PNCL. Data on PCNL complications from multiple studies revealed that a lack of standardized reporting led to a large disparity in outcomes of grading complications, which explains the wide incidence range of 20% to 83%.17-23 Fortunately, nowadays, the severity of PCNL complications is classified using the modified Clavien classification system, which allows for more standardized storage of the complications.10,11,16 Consequently, the data collection process revealed that complications under this system decreased from the previous incidence, however, serious complications remained.

The contraindications for PCNL include pregnancy, bleeding disorders, and uncontrolled urinary tract infections. PCNL can cause many complications such as bleeding, infection, pneumothorax, hydrothorax, hemothorax, urinothorax, persistent nephrocutaneous fistula, rupture of the pelvicalyceal system, small bowel perforation, liver

injury, splenic injury, and colonic perforation. A mini- review by the Clinical Research of the Endourological Society (CROES) on the topic of “Complications associated with percutaneous nephrolithotomy” reported an overall complication rate of 21.5%. This was the result from an international multi-center study of 5,803 patients conducted across 96 centers in Europe, Asia, North America, South America, and Australia. They found that the complication rate reported by the modified Clavien system was as follows: no complications (79.5%), I (11.1%), II (5.3%), IIIa (2.3%), IIIb (1.3%), IVa (0.3%),

IVb (0.2%), and V (0.03%) respectively.17 The most common minor complication was transient fever, which is consistent with the results of our study. Major PCNL complications were grades III, IV, and V of the modified Clavien system and involved renal pelvis perforation, serious bleeding, severe infection, or adjacent organ injury as mentioned above.

While PCNL demonstrated a strong therapeutic effect, it is also riskier due to its invasiveness nature and some limitations.3,18,23 For instance, it has higher complication rates, increased risk of bleeding, and can lead to perioperative blood loss which may require transfusion, embolization, or in rare instances, nephrectomy leading to a lengthy hospital stay compared to RIRS. Moreover, the prone position is often preferred in PCNL procedures, but it requires significantly more effort by an anesthesiologist during operation. As the acceptable risk in each patient may be different, PCNL may not be feasible for every situation, so minimally invasive procedures such as RIRS is much more appealing in fragile patients.

In recent times, RIRS has received more attention and has been used in staghorn stone patients in a variety of research. RIRS yields a lower stone-free rate initially but is comparable to PCNL after several staged RIRS sessions. RIRS also has fewer complications and severity. Many studies showed a decent efficacy with an 83%-93% stone-free rate after three procedures and it is able to cover a large group of patients, including the high-risk as an alternative option to standard treatment.9,24-29

In our study, we present a single-center tertiary care series of RIRS for any staghorn stones. The treatment and follow-up data were obtained retrospectively. The stone-free rates in our institutions were only 31% during the first procedure, but this increased to 59.6% after the second procedure, respectively. Since the procedure was performed in patients contraindicated for PCNL and those with complicated cases in the tertiary care center, in combination with other factors such as the small sample size, the surgeon’s experience, and case selection methods, the stone-free rate may differ from

other studies. Additionally, thirteen patients who were in the non-stone-free group stopped the procedure and switched to medical treatment divided into six, five, and two patients from the first, second, and third procedures sequentially.

RIRS complications seem to be high when we calculate in percent due to a small sample size. However, in this study, there were no serious complications like those found in PCNL, such as injury to adjacent organs or bleeding that required transfusion. This study had 2 patients (6%) of grade IIIa complication which was septicemia, this figure was higher than an usual complication for RIRS which septic complication was 0.9%.30 This because of a small sample size as well as staghorn stone is at high risk of infection according to it is mostly infected stone and the surgery requires prolong operative time regards the stone size. PCNL is still considered as the first-line therapy for kidney stones over two centimeters with a favorable stone-free rate. But, in some patients with limitations such as uncorrectable coagulopathies, impaired renal function, single kidney, morbid obesity, severe obstructive pulmonary disease, postural contracture, or those who require treatment preserving renal parenchyma, RIRS is a good choice to reduce the likelihood of complications and have an acceptable stone-free rate in multistage RIRS.

A limitation of this study was that it was a single- center, non-randomized study with a small sample size, and post-operative imaging using plain x-ray may miss small residual stones. Also, the experience of surgeons in tertiary care services may differ. Due to these reasons, the obvious limitation is the reproducibility of the results. Nevertheless, a larger sample size undergoing RIRS with preferable outcomes and usefulness of our described technique will be reviewed.

CONCLUSION

Percutaneous nephrolithotomy (PCNL) is still considered the first-line therapy for kidney stones over two centimeters with a favorable stone-free rate. But, in some patients with limitations such as uncorrectable coagulopathies, impaired renal function, single kidney, and morbid obesity, RIRS is a good choice to reduce the likelihood of serious complications and have an acceptable stone-free rate. However, a prospective study should be performed to confirm these findings.

ACKNOWLEDGEMENTS

The authors gratefully acknowledge Ms. Julaporn Pooliam and Ms. Jitsiri Chaiyatho for assistance with statistical analysis.

Potential Conflicts of Interest

There are no conflicts of interest to report. There are no sources of funding to disclose.

REFERENCES

1. Arunkajohnsak N, Taweemonkongsap T, Leewansangtong S, Srinualnad S, Jongjitaree K, Chotikawanich E. The correlation between demographic factors and upper urinary tract stone composition in the Thai population. Heliyon. 2020;6(8):e04649.

2. Yanagawa M, Kawamura J, Onishi T, Soga N, Kameda K, Sriboonlue P, et al. Incidence of urolithiasis in northeast Thailand. Int J Urol. 1997;4(6):537-40.

3. Preminger GM, Assimos DG, Lingeman JE, Nakada SY, Pearle MS, Wolf JS, Jr., et al. Chapter 1: AUA guideline on management of staghorn calculi: diagnosis and treatment recommendations. J Urol. 2005;173(6):1991-2000.

4. Diri A, Diri B. Management of staghorn renal stones. Ren Fail. 2018;40(1):357-62.

5. Blandy JP, Singh M. The case for a more aggressive approach to staghorn stones. J Urol. 1976;115(5):505-6.

6. Koga S, Arakaki Y, Matsuoka M, Ohyama C. Staghorn calculi-

   -long-term results of management. Br J Urol. 1991;68(2):122-4.

7. Turk C, Petrik A, Sarica K, Seitz C, Skolarikos A, Straub M, et al. EAU Guidelines on Interventional Treatment for Urolithiasis. Eur Urol. 2016;69(3):475-82.

8. Assimos D, Krambeck A, Miller NL, Monga M, Murad MH, Nelson CP, et al. Surgical Management of Stones: American Urological Association/Endourological Society Guideline, PART II. J Urol. 2016;196(4):1161-9.

9. Barone B, Crocetto F, Vitale R, Di Domenico D, Caputo V, Romano F, et al. Retrograde intra renal surgery versus percutaneous nephrolithotomy for renal stones >2 cm. A systematic review and meta-analysis. Minerva Urol Nefrol. 2020;72(4):441-50.

10. de la Rosette JJ, Opondo D, Daels FP, Giusti G, Serrano A, Kandasami SV, et al. Categorisation of complications and validation of the Clavien score for percutaneous nephrolithotomy. Eur Urol. 2012;62(2):246-55.

11. Shin TS, Cho HJ, Hong SH, Lee JY, Kim SW, Hwang TK. Complications of Percutaneous Nephrolithotomy Classified by the Modified Clavien Grading System: A Single Center’s Experience over 16 Years. Korean J Urol. 2011;52(11):769-75.

12. Ozden C, Oztekin CV, Pasali S, Senel S, Demirel D, Bulut S, et al. Analysis of clinical factors associated with intraoperative and postoperative complications of retrograde intrarenal surgery. J Pak Med Assoc. 2021;71(6):1666-70.

13. Tepeler A, Resorlu B, Sahin T, Sarikaya S, Bayindir M, Oguz U, et al. Categorization of intraoperative ureteroscopy complications using modified Satava classification system. World J Urol. 2014; 32(1):131-6.

14. Oguz U, Resorlu B, Ozyuvali E, Bozkurt OF, Senocak C, Unsal

    A. Categorizing intraoperative complications of retrograde intrarenal surgery. Urol Int. 2014;92(2):164-8.

15. Koras O, Bozkurt IH, Karakoyunlu AN, Celik S, Sefik E, Yarımoglu S, et al. Retrospective Analysis of the Factors Affecting Intraoperative and Immediate Postoperative Complications of Retrograde Intrarenal Surgery Classified by the Clavien and Satava Grading Systems. J Endourol. 2021;35(12):1764-72.

16. Tefekli A, Ali Karadag M, Tepeler K, Sari E, Berberoglu Y, Baykal M, et al. Classification of percutaneous nephrolithotomy

    
    

    complications using the modified clavien grading system: looking for a standard. Eur Urol. 2008;53(1):184-90.

17. de la Rosette J, Assimos D, Desai M, Gutierrez J, Lingeman J, Scarpa R, et al. The Clinical Research Office of the Endourological Society Percutaneous Nephrolithotomy Global Study: indications, complications, and outcomes in 5803 patients. J Endourol. 2011; 25(1):11-7.

18. Rudnick DM, Stoller ML. Complications of percutaneous nephrostolithotomy. Can J Urol. 1999;6(5):872-5.

19. el-Nahas AR, Eraky I, Shokeir AA, Shoma AM, el-Assmy AM, el-Tabey NA, et al. Factors affecting stone-free rate and complications of percutaneous nephrolithotomy for treatment of staghorn stone. Urology. 2012;79(6):1236-41.

20. Mousavi-Bahar SH, Mehrabi S, Moslemi MK. Percutaneous nephrolithotomy complications in 671 consecutive patients: a single-center experience. Urol J. 2011;8(4):271-6.

21. Segura JW, Patterson DE, LeRoy AJ, Williams HJ, Jr., Barrett DM, Benson RC, Jr., et al. Percutaneous removal of kidney stones: review of 1,000 cases. J Urol. 1985;134(6):1077-81.

22. Rassweiler JJ, Renner C, Eisenberger F. The management of complex renal stones. BJU Int. 2000;86(8):919-28.

23. Taylor E, Miller J, Chi T, Stoller ML. Complications associated with percutaneous nephrolithotomy. Transl Androl Urol. 2012; 1(4):223-8.

24. Al-Qahtani SM, Gil-Deiz-de-Medina S, Traxer O. Predictors of clinical outcomes of flexible ureterorenoscopy with holmium

    laser for renal stone greater than 2 cm. Adv Urol. 2012;2012:543537.

25. Pevzner M, Stisser BC, Luskin J, Yeamans JC, Cheng-Lucey M, Pahira JJ. Alternative management of complex renal stones. Int Urol Nephrol. 2011;43(3):631-8.

26. Martí José Luis P, Ituren Amparo G, González Lorena V. RESULTADOS ACTUALES DE LA CRIR Y COMPARACIÓN

    CON NLPC. Archivos Españoles de Urología. 2017;70(1):147- 54.

27. Breda A, Ogunyemi O, Leppert JT, Lam JS, Schulam PG. Flexible ureteroscopy and laser lithotripsy for single intrarenal stones 2 cm or greater--is this the new frontier? J Urol. 2008;179(3): 981-4.

28. Cohen J, Cohen S, Grasso M. Ureteropyeloscopic treatment of large, complex intrarenal and proximal ureteral calculi. BJU Int. 2013;111(3 Pt B):E127-31.

29. Nualyong C, Sathidmangkang S, Woranisarakul V, Taweemonkongsap T, Chotikawanich E. Comparison of the outcomes for retrograde intrarenal surgery (RIRS) and percutaneous nephrolithotomy (PCNL) in the treatment of renal stones more than 2 centimeters. Insight Urology. 2019;40(1):9-14.

30. Hansomwong T, Nualyong C, Taweemonkongsap T, Amornvesukit T, Phinthusophon K, Jitpraphai S, et al. Perioperative Outcomes of Retrograde Intrarenal Surgery (RIRS) Treatment of Renal Calculi in Siriraj Hospital. J Med Assoc Thai. 2017; 100: 144- 149

Validity and Reliability of the Thai version of the Family Dermatology Life Quality Index

Kanokvalai Kulthanan, M.D., Papapit Tuchinda, M.D., Leena Chularojanamontri, M.D., Chuda Rujitharanawong, M.D., Waratchaya Panjapakkul, M.D.

Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.

ABSTRACT

Objective: This study aimed to investigate the validity and reliability of the Thai version of FDLQI.

Materials and Methods: Patients and their accompanying family members attending the Dermatology Outpatient Clinic at Siriraj Hospital were asked to complete the Dermatology Life Quality Index (DLQI), FDLQI, and the global question of their QoL (GQoL). The severity of the disease was assessed by physicians, the patients and the family members of the patients. Results: One hundred family members accompanying 92 patients with dermatological diseases (63% with inflammatory skin diseases and 37% with non-inflammatory skin diseases) were included. The mean age of the family members was 43.5±12.1 years and 70% were women. They had been mostly employed (74%) and graduated from universities

(65%). Validity was demonstrated by a positive correlation between FDLQI and GQoL scores (rs=0.695, P<0.001), and between FDLQI and severity of the patient’s disease (rs=0.578, P<0.001) as evaluated by family members. The FDLQI showed high internal consistency (Cronbach’s alpha=0.84) and test-retest reliability (ICC= 0.85).

Conclusion: The construct validity, internal consistency, and test-retest reliability of the Thai FDLQI demonstrated acceptable validity and reliability. The Thai version of FDLQI can be used to assess the QoL of family members of patients with any dermatological diseases.

Keyword: Validity; reliability; Family Dermatology Life Quality Index; FDLQI (Siriraj Med J 2023; 75: 369-376)

INTRODUCTION

Dermatological diseases such as urticaria, atopic dermatitis, psoriasis, epidermolysis bullosa, acne, and hair disorders can have a tremendous impact on mental health of patients, sometimes even more than other physical diseases.1-4 This impact may not only affect patients, but also cause a negative impact on their close individuals, especially their close family members and partners.2,5 Many instruments were developed aimed at capturing and measuring quality of life (QoL) of family members of patients with dermatological diseases in order to improve holistic care to a patient as much as possible. Moreover, this dimension has grown much of interest during the

last two decades. The Family Dermatology Life Quality Index (FDLQI) is one of the questionnaires designed to measure the QoL of family members of patients affected by dermatologic diseases.6 It was originally developed in English7 and was translated and validated for use in many countries, for example, Japan8, Iran9, Ukraine10, etc. This study aimed to investigate the validity and reliability of the Thai version of FDLQI.

MATERIALS AND METHODS

The protocol of this study was approved by the Siriraj Institutional Review Board (COA no. Si 905/2021). Patients and their accompanying family members or

Corresponding author: Leena Chularojanamontri E-mail: leenajim@gmail.com

Received 6 January 2023 Revised 18 March 2023 Accepted 19 March 2023 ORCID ID:http://orcid.org/0000-0001-6625-6445 https://doi.org/10.33192/smj.v75i5.260735

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

partners attending the Dermatology Outpatient Clinic at Siriraj Hospital were asked if they were willing to participate in the study. Informed consent was obtained if the patient agreed to participate. The inclusion criteria for the family members or partners of the patients were:

(i) 18 years or older, (ii) the first-degree relative who lived in the same household, and (iii) the ability to read and understand Thai language. Family members or partners of patients who had other severe concomitant diseases other than dermatological disease were excluded.

Questionnaires

FDLQI: is a questionnaire that was developed by Basra et al. to measure the QoL of family members or partners of patients with dermatological diseases in 10 aspects over the past month. Ten aspects comprise (i) emotional, (ii) physical well-being, (iii) relationships, (iv) reactions of people, (v) social life, (vi) leisure activities,

(vii) burden of care, (viii) extra housework, (ix) job / study and (x) additional expenditure. Each aspect will be evaluated by each question, which will be rated by the score 0 = ‘not at all / not relevant’, 1 = ‘a little’, 2 = ‘quite a lot’ and 3 = ‘very much’. Therefore, the score ranges from 0 to 30, indicating ‘no’ and ‘maximum’ impacts on quality of life, respectively.6

Dermatology Life Quality Index (DLQI): is a questionnaire that was developed by Finlay A.Y. and Khan

G.K.11 It measures the QoL of patients with dermatological diseases over one week. Six aspects of the 10 questions include (i) symptoms and feelings, (ii) daily activities,

(iii) social or leisure activities, (iv) work or study, (v) personal relationships, and (vi) effect of treatment. The total DLQI score ranges from 0 to 30 (0 to 3 points for each question), and the higher the score reflects a greater impact on the patient’s QoL. This questionnaire has also received the formal permission of the developers to translate into Thai and has already been validated and widely used in Thailand.12

Global question: is a simple question used to assess the severity and quality of life of the disease over the past month on a numerical rating scale, with 0 and 10 indicating ‘no’ and ‘worst’, respectively.

Translation process of the FDLQI

After receiving permission for the translation into Thai language from the FDLQI developers, our translation process was performed according to their instructions. The translation of the original English language into Thai was carried out by two independent translators who were bilingual. Then, these two Thai versions were read and discussed by four Thai dermatologists (KK, LC, PT,

CR) resulting in minor changes to make a conceptual equivalence to the original questionnaire. Afterwards, this version was independently translated back into English by two bilingual English-language experts, who were unaware of the original version. Finally, the same four Thai dermatologists read and discussed both translations in order to find a consensus version. After the backtranslation for FDLQI was approved by one of the developers, a cognitive debriefing was performed in family members of five patients comprised: 1) a 30-year-old woman accompanying her husband with pityrosporum folliculitis for two months, 2) a 54-year- old woman accompanying her daughter with chronic eczema of the left foot for one month, 3) a 28-year-old male accompanying her father with androgenic alopecia for five years, 4) a 58-year-old woman accompanying her mother with xerotic eczema for 18 months and 5) a 60-year-old male accompanying his daughter with post inflammatory hyperpigmentation from acne for 4 months. All agreed that the form of the questions was clear and easily understandable, leading to no change for the final Thai version of the FDLQI.

Participants

A total of 100 family members accompanying 92 patients with dermatological diseases were included. On the visit date, patients were asked to rate their QoL using DLQI and a global QoL question for patients (GQoLP). Their family members were also asked to complete their QoL by the FDLQI and a global QoL question for family members (GQoLF). The physicians, patients themselves, and their family members completed a global question regarding the severity of the patient’s disease. After finishing all processes within 10-15 minutes, patients’ family members were asked their convenient time for a telephone interview to complete another FDLQI sheet the next day for reliability of the test.

Psychometric Evaluations

Validity: was investigated by comparing the test to other tests that measure the relevant construct. The correlation between patient evaluation scores (DLQI, GQoLP and a global question for patient’s disease severity) and the assessment scores of family members (the Thai version of FDLQI, GQoLF, a global question for patient’s disease severity) were investigated using Spearman’s rank correlation. A correlation coefficient of approximately 0.3, 0.5, and 0.7 was interpreted as a weak, moderate, and strong correlation, respectively.13 We expected the highest correlation between the Thai version of the FDLQI and GQoLF.

Reliability: Reliability was investigated by Cronbach’s alpha and the intraclass correlation coefficient (ICC). The Cronbach value of < 0.5, 0.5- 0.6, 0.6-0.7, 0.7-0.8, 0.8–0.9,

>0.9 was interpreted as unacceptable, poor, questionable, acceptable, good and excellent, respectively.14 An ICC of

0.5 to 0.7, and >0.7 was considered to indicate moderate to good and excellent reproducibility, respectively.15 All statistical analyses were performed with PASW Statistics version 18.0 (SPSS, Inc., Chicago, IL, USA). A p-value

(P) < 0.05 was considered statistical significance.

RESULTS

Of 100 family members with a mean age of 43.5

± 12.1 years, 70% were women (Table 1). Thirty-one participants were parents of patients. They had been mostly employed (74%) and graduated from universities (65%). On the other hand, 54 (58.7%) of the 92 patients were men and the mean age was 42.8 ± 21.0 years. The median duration of their dermatological diseases was 12 months. Fifty-eight patients (63.0%) were diagnosed with inflammatory diseases, while the remaining (34/92; 37.0%) had non-inflammatory diseases. Eczema (13/92; 14.1%) and androgenic alopecia (11/92; 12.0%) were primary diseases of each group, respectively.

The total scores of the FDLQI ranged from 0 to

24. Fig 1 shows the percentage of each response to each item. The responses to most items (except burden of care and extra expenditure) were not at all/not relevant, and ‘a little’. The burden of care was the most frequently reported problem of family members. The minimum, maximum, and median scores of each questionnaire are shown in Table 2. The median total score of DLQI and FDLQI was equal. Comparison of total scores between inflammatory and non-inflammatory diseases, the median total score of DLQI score of patients with inflammatory diseases (score = 6) was significantly higher than that of patients with non-inflammatory diseases (score = 3) (P < 0.03). However, the median total score of FDLQI (score = 4) with inflammatory disease was lower than that of patients with noninflammatory diseases (score = 5.5) but there was no statistical significance (P = 0.840) (data not shown).

Table 3 shows the correlations between FDLQI and other instruments. As expected, there was a high correlation between FDLQI and GQoLF (rs = 0.695, P < 0.001). The correlation between FDLQI and the severity of the disease of the patients as assessed by family members was moderate (rs = 0.578, P < 0.001). No and weak correlations were found between FDLQI, DLQI, GQoLP, and the severity of the diseases of the patients as assessed by the patients themselves and the physicians.

The reliability of internal consistency according to the Cronbach alpha scale was 0.84 and this was not significantly improved by deleting individual items (0.81– 0.84) (Table 4). Regarding the reliability of the test-retest, there were 79 family members who responded to the FDLQI retest. The intraclass correlation value for the total FDLQI score was 0.85 which indicated good reproducibility. The difference scores of the test and retest ranged from 0 to 7 with a mean score of 1.16 (SD = 2.4).

DISCUSSION

The burden of skin disease is defined into three dimensions: “now”, “long-term” and “family members”.16 The first two affect patients, while the third dimension causes a burden to partners and family members. As the patient is the center, the first two dimensions have been extensively explored, whereas there are relatively limited data for the third dimension. A systematic review of dermatology-specific instruments to evaluate the impact of dermatological conditions on family and caregivers found that there were nine instruments. Eight of them are specific instruments for dermatologic diseases (4 for atopic dermatitis, 2 for psoriasis, 1 for epidermolysis bullosa acquisita, 1 for ichthyosis). Only one of them is the generic questions for dermatologic diseases, the FDLQI.17 The FDLQI has been used in family members of patients with epidermolysis bullosa3, atopic dermatitis10,18, psoriasis19,20, vitiligo21,22, leg ulcers23, and pemphigus.24 One advantage of FDLQI is that it can be used to compare the QoL of family members under different skin conditions. In this study, the total FDLQI score ranged from

0 to 24, with a score of 0 reported in 2% of the family members. This demonstrated that there may be no floor or ceiling effect in the Thai version of FDLQI. However, to our knowledge, there are no standard criteria for floor and ceiling effects. McHorney et al.25 proposed that both effects should be less than 15% and this was supported by other studies26,27, while other studies proposed that number should be 25%.28,29 The median total score of DLQI and FDLQI in our study was 4.5 out of the maximum score of 30, which was quite low. These corresponded to those of the United Kingdom6 and Japan.8 The reason may be that all the studies were carried out in the outpatient clinic where most patients tend to have mild to moderate disease severity. Additionally, the median duration of the disease of the patients in this study was 12 months. Sajedianfard et al. reported that longer disease duration and more recurrences could decrease the FDLQI score.24 The construct validity of the FDLQI was shown by

a strong and moderate positive correlation with GQoLF and the severity of the disease of the patients rated by

TABLE 1. Demographic data of patients and their family members

Patients (N=92)*

Sex

*One patient could be accompanied by more than one of their family members

aatopic dermatitis, candidiasis, chelitis, chronic paronychia, discoid lupus erythematosus, insect bite reaction, kaposi hemagioendothelioma, lichen simplex chronicus, lupus profundus, pyoderma gangrenosum, rosacea, sporotrichosis, systemic lupus erythematosus, urticarial vasculitis

baqugenic pruritus, basal cell carcinoma, chronic arsenism, dermatofibroma, filler complication, hyperhydrosis, keloid, melasma, onychomychosis, pearly penile papules

TABLE 2. Score of each questionnaire

Fig 1. Scores and responses distribution. A, FDLQI and DLQI Score Distribution. B, The percentage of each response to each FDLQI’s item

Abbreviations: DLQI: Dermatology Life Quality Index; FDLQI: Family Dermatology Life Quality Index

Abbreviations: DLQI; Dermatology Life Quality Index, FDLQI; Family Dermatology Life Quality Index, GqoLF; global QoL question for family members, GqoLP; global QoL question for patients, P; percentile

TABLE 3. Validity of Family Dermatology Life Quality Index (FDLQI) to other questionnaires

Physician’s assessment

Global question of patient’s disease severity 0.318 0.002*

*A p-value of less than 0.05 indicates statistical significance

Abbreviations: DLQI; Dermatology Life Quality Index, FDLQI; Family Dermatology Life Quality Index, GqoLF; global QoL question for family members, GqoLP; global QoL question for patients

TABLE 4. Reliability analysis of the items of the Family Dermatology Life Quality Index (FDLQI)

Abbreviation: FDLQI; Family Dermatology Life Quality Index

family members, respectively. This is in line with that of the Japanese version.8 As expected, the DLQI score of patients with inflammatory diseases was significantly higher than those with non-inflammatory diseases.9,30 However, this pattern was not consistent with the FDLQI results. The Thai version of the FDLQI showed high reliability, which corresponds to the original version and those of other countries, including Japan, Iran and

Ukraine.31 The Cronbach alpha was not significantly improved by removing any item of the FDLQI. Basra et al.6 and Higaki et al.8 also demonstrated that the FDLQI could be used to monitor the QoL of family members of patients with chronic skin diseases, such as eczema, psoriasis, and squamous cell carcinoma, etc. In a follow- up period of three to six months, the FDLQI could detect changes overtime.

Different culture, socioeconomic status, and educational levels could reflect different effects on the QoL of individuals.3,9,32,33 This could be one of the reasons that the correlation between the DLQI and the FDLQI score in Thailand and other countries was not very close. The DLQI was completed by a patient while the FDLQI was completed by a patient’s family member. During the process of our study, some participants explained why they had rated those scores. For example, some patients had horrible acnes while their family members felt little or no effect on their lives. In contrast, some family members, especially parents and partners, felt very worried and used a lot of time to care for the skin diseases (ex. alopecia areata, basal cell carcinoma, and pearly penile papules) while the patients did not feel that it was the problem of their lives.

Some limitations of this study should be noted. First, it had a small sample size. Second, it was carried out only in only urban area of Thailand, where daily life, culture, socioeconomic status, and educational levels are much different from the rural area.34,35

CONCLUSION

All three dimensions of skin burden must be taken into account to provide the best holistic care to a patient. FDLQI is one of the most widely used instruments for measuring the QoL of the dermatological patients. This study shows the acceptable validity and reliability of the Thai version of the FDLQI. It is a generic questionnaire that can be used to assess the QoL of family members of patients in any dermatological disease.

ACKNOWLEDGMENTS

The authors thank Assistant Professor Chulaluk Komoltri for statistical analysis consultation.

Data Availability

The data used to support the findings of this study are included within the article.

REFERENCES

1. Karimkhani C, Dellavalle RP, Coffeng LE, Flohr C, Hay RJ, Langan SM, et al. Global Skin Disease Morbidity and Mortality: An Update From the Global Burden of Disease Study 2013. JAMA Dermatol. 2017;153:406-12.

2. Montero-Vilchez T, Sánchez-Díaz M, Martinez-Lopez A, Arias-Santiago S. Quality of Life in Patients with Skin Disease and Their Cohabitants. Health-Related Qualityof Life- Measurement Tools, Predictors and Modifiers. doi:10.5772/intechopen.97450

3. Chogani F, Parvizi MM, Murrell DF, Handjani F. Assessing the quality of life in the families of patients with epidermolysis bullosa: The mothers as main caregivers. Int J Womens Dermatol. 2021;7:721-6.

4. Lifschitz C. The impact of atopic dermatitis on quality of life. Ann Nutr Metab. 2015;66 Suppl 1:34-40.

5. Rees J, O’Boyle C, MacDonagh R. Quality of life: impact of c hronic illness on the partner. J R Soc Med. 2001;94:563-6.

6. Basra MK, Sue-Ho R, Finlay AY. The Family Dermatology Life Quality Index: measuring the secondary impact of skin disease. Br J Dermatol. 2007;156:528-38.

7. Basra MK, Edmunds O, Salek MS, Finlay AY. Measurement of family impact of skin disease: further validation of the Family Dermatology Life Quality Index (FDLQI). J Eur Acad Dermatol Venereol. 2008;22:813-21.

8. Higaki Y, Tanaka M, Futei Y, Kamo T, Basra MKA, Finlay AY. Japanese version of the Family Dermatology Life Quality Index: Translation and validation. J Dermatol. 2017;44:914-9.

9. Safizadeh H, Nakhaee N, Shamsi-Meymandi S, Pourdamghan N, Basra MK. Preliminary reliability and validity of Persian version of the Family Dermatology Life Quality Index (FDLQI). Qual Life Res. 2014;23:869-75.

10. Chernyshov PV, Kaliuzhna LD, Reznikova AA, Basra MK. Comparison of the impairment of family quality of life assessed by disease-specific and dermatology-specific instruments in children with atopic dermatitis. J Eur Acad Dermatol Venereol. 2015;29:1221-4.

11. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical measure for routine clinical use. Clin Exp Dermatol. 1994;19:210-6.

12. Kulthana K JS, Wanitphakdeedecha R. The validity and reliability of the dermatology life quality index (DLQI) in Thais. Thai J Dermatol. 2004;20:113-23.

13. Nunnaly JC, BI. Psychometric theory. 3rd ed: NewYork: Mc Graw-Hill; 1994.

14. Schmitt N. Uses and Abuses of Coefficient Alpha. Psychological Assessment. 1996;8:350-3.

15. Gourraud PA, Le Gall C, Puzenat E, Aubin F, Ortonne JP, Paul CF. Why statistics matter: limited inter-rater agreement prevents using the psoriasis area and severity index as a unique determinant of therapeutic decision in psoriasis. J Invest Dermatol. 2012; 132:2171-5.

16. Finlay A. The three dimensions of skin disease burden: ‘Now’, ‘long term’ and ‘family’. Br J Dermatol. 2013;169:963-4.

17. Sampogna F, Finlay AY, Salek SS, Chernyshov P, Dalgard FJ, Evers AWM, et al. Measuring the impact of dermatological conditions on family and caregivers: a review of dermatology- specific instruments. J Eur Acad Dermatol Venereol. 2017;31: 1429-39.

18. Köse S, Akelma Z, Özmen S. Severity of disease and the quality of life indexes in infants with atopic dermatitis. Allergol Immunopathol (Madr). 2022;50:55-61.

19. Martínez-García E, Arias-Santiago S, Valenzuela-Salas I, Garrido-Colmenero C, García-Mellado V, Buendía-Eisman A. Quality of life in persons living with psoriasis patients. J Am Acad Dermatol. 2014;71:302-7.

20. Kim E, Fischer G. Relationship between PASI and FDLQI in paediatric psoriasis, and treatments used in daily clinical practice. Australas J Dermatol. 2021;62:190-4.

21. Agarwal S, Jain C, Shaafie HI, Khalid A, Singh A. Impact on quality of life of family members of vitiligo patients in North India: A cross-sectional study using family dermatology life quality index. Indian J Dermatol Venereol Leprol. 2021;87: 869-72.

    
    

22. Bin Saif GA, Al-Balbeesi AO, Binshabaib R, Alsaad D, Kwatra SG, Alzolibani AA, et al. Quality of life in family members of vitiligo patients: a questionnaire study in Saudi Arabia. Am J Clin Dermatol. 2013;14:489-95.

23. Kouris A, Christodoulou C, Efstathiou V, Chatzimichail I, Zakopoulou N, Zouridaki E. Quality of life in Greek family members living with leg ulcer patients. Wound Repair Regen. 2015;23:778-80.

24. Sajedianfard S, Handjani F, Saki N, Heiran A. Family dermatology life quality index in patients with pemphigus vulgaris: A cross- sectional study. Indian J Dermatol Venereol Leprol. 2021;87: 375-8.

25. McHorney CA, Tarlov AR. Individual-patient monitoring in clinical practice: are available health status surveys adequate? Qual Life Res. 1995;4:293-307.

26. Terwee CB, Bot SD, de Boer MR, van der Windt DA, Knol DL, Dekker J, et al. Quality criteria were proposed for measurement properties of health status questionnaires. J Clin Epidemiol. 2007;60:34-42.

27. Wamper KE, Sierevelt IN, Poolman RW, Bhandari M, Haverkamp

    D. The Harris hip score: Do ceiling effects limit its usefulness in orthopedics? Acta Orthop. 2010;81:703-7.

28. Uttl B. Measurement of Individual Differences: Lessons From

    Memory Assessment in Research and Clinical Practice. Psychol Sci. 2005;16(6):460-7.

29. Raat H, Landgraf JM, Oostenbrink R, Moll HA, Essink-Bot ML. Reliability and validity of the Infant and Toddler Quality of Life Questionnaire (ITQOL) in a general population and respiratory disease sample. Qual Life Res. 2007;16:445-60.

30. Zhang X-J, Wang A-P, Shi T-Y, Zhang J, Xu H, Wang D-Q, et al. The psychosocial adaptation of patients with skin disease: a scoping review. BMC Public Health. 2019;19:1404.

31. Ware JE, Jr., Gandek B. Methods for testing data quality, scaling assumptions, and reliability: the IQOLA Project approach. International Quality of Life Assessment. J Clin Epidemiol. 1998;51:945-52.

32. Yun J, Katelaris CH, Weerasinghe A, Adikari DB, Ratnayake C. Impact of chronic urticaria on the quality of life in Australian and Sri Lankan populations. Asia Pac Allergy. 2011;1:25-9.

33. Knafl KA, Gilliss CL. Families and Chronic Illness: A Synthesis of Current Research. J Fam Nurs. 2002;8:178-98.

34. Ariyaarpakamol N. Urban-rural inequality in Thailand: Differences in characteristics or returns? Kasetsart J Soc Sci. 2019;40:32-9.

35. Hitokoto H, Takahashi Y, Kaewpijit J. Happiness in Thailand: Variation between urban and rural regions. Psychologia. 2014;57:229-44.

Adverse Events of Traditional Medicines and Herbal Products in the Thai Health Product Vigilance Center Database and the Ayurved Clinic of Applied Thai Traditional Medicine, Siriraj Hospital

Suvimol Niyomnaitham, M.D.,*,**, Narichat Chuensakun, B.ATM.***, Slita Prachakit, B.ATM.***, Chidapa Pakjamsai, B.ATM.***, Pravit Akarasereenont, M.D., Ph.D.*,***

*Department of Pharmacology, Faculty of Medicine Siriraj Hospital, **Siriraj Institute of Clinical Research, Faculty of Medicine Siriraj Hospital, Mahidol University, ***Center of Applied Thai Traditional Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.

ABSTRACT

Objective: The aim of this study was to categorize adverse events (AEs) and symptoms related to traditional medicines (TMs) and herbal products (HPs) using the Thai Vigibase program (TVP).

Materials and Methods: TVP collected spontaneous AE reports including causality assessment of medical products in Thailand. For prospective data, Naranjo’s algorithm (NJA) was used to determine the level of causality.

Results: There were a total of 1,133 AE case reports extracted from TVP and featured 1,229 TMs/HPs (310 TMs/ HPs names) and 1,592 symptoms (204 symptom names). Andrographis paniculata was the product most frequently linked to AEs, with six cases of confirmed urticaria, 37 probable cases, and 24 possible causalities, 15 patients were given 23 TMs/HPs and this related to 33 AEs. The Ya Hom No.24 Tablets had the most reported AEs at 17.4% with only one causality, which was most probably linked to chest burning pain. There was also one case of herbal decoction relieving menopausal symptoms that was certainly related to chest fullness, feeling hot and cold, suffocation feeling, and sweating increase. Ayurved Siriraj Brand Ya Lom No.65 Pills, also reported one case that was linked to fatigue and drowsiness.

Conclusion: Reports from both data sources found a similar pattern in AE type and TMs/HPs. Naranjo’s algorithm might be one of useful tools to help assess the causality between TMs/HPs and AEs. The results of this study serve as a good reference for causality between TMs/HPs and their AEs for all Thai traditional medicine practitioners.

Keywords: Traditional medicine; herbal product; adverse event; symptom name; and Naranjo’s algorithm (Siriraj Med J 2023; 75: 377-391)

INTRODUCTION

Traditional medicines (TMs) and herbal products (HPs) are increasingly being used across the world. The Thai herbal industry grew from $US27 million in 2003 to $US300 million in 2014.1,2 This acceleration of over

10% growth per year was the result of global exports of.2 Although a great deal of research has been carried out to prove the benefits of TMs/HPs, adverse events (AEs) remain a concern. Minimal adverse effects of TMs/ HPs have been recorded worldwide and systemically

Corresponding author: Pravit Akarasereenont E-mail: pravit.auk@mahidol.edu

Received 24 February 2023 Revised 18 March 2023 Accepted 27 March 2023 ORCID ID:http://orcid.org/0000-0001-5743-3251 https://doi.org/10.33192/smj.v75i5.261512

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

categorized.3-5 An understanding of AEs associated with TMs/HPs is essential for accurate prescriptions and to ensure user safety. Global organizations, such as the World Health Organization (WHO), have stored safety profile data of TMs/HPs use, including AE reports.6 Regulatory authorities in many countries such as the Therapeutic Goods Administration (TGA) in Australia or even the China Food and Drug Administration (CFDA) in China, have tried to establish prospective surveillance in order to gain an understanding of the frequency, severity and causes of AEs involving TMs/HPs.7-9 As a result of continuous data collection in studies from around the world, there is an abundance of results regarding herbal safety. For example, several studies have examined possible AEs linked to TMs/HPs through regulatory pharmacovigilance programs. A study of ADRs in Brazil10, a prospective study with complementary medicine inpatients in Germany11 and a study of AE using complementary and alternative medicine (CAM) products in Singapore12 all looked at herbal drug ingredients.

In 1980, the Ministry of Public Health of Thailand began drug monitoring in hospitals with the founding of the Health Product Vigilance Center (HPVC), which in 1983 came under Thai Food and Drug Administration (Thai FDA). The Thai Vigibase Program (TVP) was created to collect AE reports of health products, including HPs from all over the country.13 In Thailand, pharmacovigilance studies on the safety of herbal products have increased, especially of Traditional Thai medicine. A study conducted in 2000 at Lampang Hospital, in the north of Thailand reported hepatotoxic effects in Type 2 diabetes patients treated with Tinospora crispa.14 Retrospective data from TVG between 2001-2012 described AEs, including hypersensitivity reactions to Andrographis products.15 Studies looking at some specific TMs/HPs and serious AEs used the TVG which collects all AEs from health products, including TMs/HPs.16,17 However, in this study, there was a plan to collect and analyze AE reports of HPs from two dimensions: retrospective data from database in Thailand and prospective visitors to Ayurved Clinic (AC) at Siriraj Hospital.

The Ayurved Clinic (AC) of Applied Thai Traditional Medicine under the Center of Applied Thai Traditional Medicine (CATTM), Faculty of Medicine Siriraj Hospital provides all types of traditional Thai treatments, including TMs/HPs to patients. Ingredients of TMs/HPs at the AC are not only known for their efficacy, but also manufactured following factory qualified standards or Good Manufacturing Practice (GMP) and the Pharmaceutical Inspection Co- operation Scheme (PICS). However, adverse effects caused by TMs/HPs need to be classified and incorporated with

the national database of Thailand. Following a previous AE study, this report was designed to continuously and retrospectively collect AEs related to TMs/HPs.16 This prospective collection of AEs at the AC provides a more complete picture of patient information compared to retrospective data of the former study. Therefore, the aim of this study was to describe characteristics of AEs using TVP and patients’ data from AC.

MATERIALS AND METHODS

This study was approved by the Ethics Committee for Research in Humans via certificate of approval No. Si 410/2015, and ran at the Faculty of Medicine Siriraj Hospital between 2015 and 2017. There were two sets of data, including a retrospective part that looked at TVP data from the national database and a prospective part in which patients experienced AEs as a result of TMs/ HPs at the AC.

Thai Vigibase Program (TVP)

Retrospective data was extracted from TVP, a database that collects spontaneous AE reports in the country. The reports were submitted either as an electronic form via an online reporting system or in paper format to the Health Product Vigilance Center (HPVC), Thai Food and Drug Administration (Thai FDA). The HPVC shares this data for use in pharmacovigilance studies. Each data point in the reports extracted characteristics of patients such as, names of products, terms and characteristics of AEs between January 2009 and July 2015.

Ayurved Clinic (AC)

A prospective study at the AC, Faculty of Medicine Siriraj Hospital was conducted between August 2015 and March 2016 and the prevalence of AEs in patients prescribed TMs/HPs was recorded. AEs were assessed by doctors who specialize in traditional Thai medicine and Western physicians, including follow-ups by telephone to record patients’ sign and symptoms. The World Health Organization’s Adverse drug Reaction Terminology (WHO-ART) was used to explain symptoms linked to AEs. Naranjo’s algorithm (NJA) is a widely used tool among pharmacists to assess the ADRs of patients and the causality of adverse drug reactions through the answering of 10 questions.18 Each question was answered and then categorized according to a scoring system divided into four levels of causality, including “Certain”, “Probable”, “Possible”, and “Unlikely”. The total score is shown as level of the causal relationship [9-13 points = certain, 5-8 points = probable, 1-4 point (s) = possible, or less than 1 point = unlikely/doubtful].18,19

Data analysis

Retrospective data from the TVP was imported into Microsoft Excel for data generation and preliminary analysis. The SPSS program was used for statistical analysis.20 Descriptive statistics including mean, mode, and frequency were used to describe data in both retrospective and prospective studies.

RESULTS

Retrospective Results from Thai Vigibase Program and Prospective Results from Ayurved Clinic

Results from the TVP between January 2009 and July 2015 revealed, 1,131 patient reports, and a total of 1,229 products (310 product names) associated with 1,592 symptoms (204 symptom names). Some of the reports had just one product linked to one symptom, while some had one product linked to two or more symptoms. Some products also had contained more than one symptom associated to it.

According to data from the AC over the eight-month period from August 2015 to March 2016, 9,959 visitors were prescribed TMs/HPs. Of these, 15 visitors (0.15%) informed of an AE linked to clinical use of TMs/HPs use. Five of them had repeated AE after retaking the same products. There were 23 products (17 product names) linked to 33 symptoms (29 symptom names) and some

of the reports were the same as in TVP or products that had more than one AE linked to it.

Fig 1 shows the characteristics of reports and patients in TVP and AC. The report characteristics include type, quality and seriousness. According to characteristics, data from the TVP and AC were presented as spontaneous in quality level 2 and non-serious events. All reports from AC were of the spontaneous type. No clinical trials have been performed using either sets of data. Referring to the seriousness of AEs, one “death” was associated to an AE in TVP. The most serious reported AE in TVP were “Initial or prolongation of hospitalization”, which was similar to reports from AC where two serious AEs in this category were reported. According to patient characteristics from both sets of data, most of the patients were female and outpatient. All AE cases at the AC were outpatients. The age of TVP-patients mostly ranged from 46-60 whereas it was 61-75 at the AC.

Fig 2 shows the number, name and type of AE reported in products in TVP. The AE reports extracted 310 products, consisting of 64 known and 246 unknown ingredients, and 1,229 product reports. The 246 unknown ingredients may have been repeatedly reported by different events, so the exact total of unknown product names might be less than 246. The types of products included 27 single herbs and 37 herbal formulas. The single herb

Fig 1. Report characteristics and patients from the Thai Vigibase Program between January 2009 and July 2015 and Ayurved Clinic between August 2015 and March 2016.

Fig 2. Products associated with adverse events from the Thai Vigibase Program between January 2009 and July 2015.

consisted of one HP while herbal formulas contained multiple single herbs. For the single herbs, the products were reported as scientific names, including their common names. The single herb product “Andrographis paniculata”, had the most AE associated with it. The top five on the chart mostly show four single herbs, and one herbal formula known as “Ya Sa Hat Sa Ta Ra”. Although “Ya Sa Hat Sa Ta Ra” ranked fifth in the chart, it reported the most AEs among the herbal formula products. As seen in Table 2, the top 10 included 11 products in total. “Ya Ka Sai Sen” had and equal number of reports to “Zingiber cassumunar” in 10th place. The top 10 in the chart includes three herbal formulas “Ya Sa Hat Sa Ta Ra”, “Ya Khieow”, and “Ya Ka Sai Sen”.

Table 1 shows the 11 products that had the most reported AEs, causalities, and symptom names. Each product had four levels of causalities, including an unspecified level. The four levels were; certain, probable, possible and unlikely. Each was calculated using Naranjo’s algorithm assessment. The unspecified level included products that reported no causality. Most of the symptoms associated with these products fell in the probable level. In first place was “Andrographis paniculata”, which mostly led to urticaria. In second place was “Curcuma longa”, which mostly led to rash. However, for “Ya Sa Hat Sa Ta Ra”, “Cassia angustifolia or Senna alexandrina”, “Momordica charantia”, “Ya Ka Sai Sen”, and “Zingiber cassumunar”, there was no data at the certain level. Among all the data in the table, “Andrographis paniculata” was the only product to have an unspecified causality of two symptoms.

Fig 3 shows the name, type and the number of product reports from the AC. A total of 17 products reported 23 AEs. Of this, 17 TMs/HPs were single herbs and the rest herbal formulas. All products were named after the “Ayurved Siriraj Manufacturing Unit of Herbal Medicine and Products” so that reported AEs had a registered name even if there was no scientific name of a single herb. The mode of administration included pills, capsules, tablets and three different formulas of decoction. Almost all of the 17 products were herbal formula, except for “Ayurved Siriraj Brand Chum Hed Ted Herbal Tea Infusion”, which was the only single herb causing AE. “Ayurved Siriraj Brand Ya Hom No.24 Tablets”, a herbal formula was the product that reported the most AEs. In second place for AEs were three products, “Ayurved Siriraj Brand No.11 Antiflatulent Tablets”, “Ayurved Siriraj Brand No.39 Antiflatulent Tablets” and “Ya Med Kae Nam Luang Sia, Ayurved Siriraj Brand”. Most of the products were marked for internal-use except Ayurved Siriraj Brand Medicated Balm formula 1, which was meant for external use.

Table 2 shows the 17 products that had an AE associated with causalities and symptoms at the AC. “Ayurved Siriraj Brand Ya Hom No.24 tablets” had the most reported AEs. However, the “probable” category had the highest level of causalities in most products. Only two products reported a certain level of symptoms. “Herbal decoction relieving menopausal symptoms” was certainly related to chest fullness, feeling hot and cold, suffocation feeling, and sweating increase. “Ya Lom No.65 Pills, Ayurved Siriraj Brand” was also certainly related to drowsiness and fatigue.

No.

Product Report

No. (%) [n=1,229]

Level of

Causalities

Symptom Name (n)

[n=1,732]

TABLE 1. A list of the 11 products that reported the most adverse events with level of causalities, and symptom names from the Thai Vigibase Program between January 2009 and July 2015.